Anti-overingestion dosage forms

ABSTRACT

Described herein are abuse deterrent oral pharmaceutical compositions, methods for making the same, and methods of treatement using such compositions. In particular, oral pharmaceutical compositions that mitigate the risk of overingestion of one or more active pharmaceutical ingredients are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/341,143, which was filed on Nov. 2, 2016, and which claims priorityto U.S. Provisional Patent Application No. 62/250,284, filed on Nov. 3,2015, each of which are incorporated by reference herein in theirentirety.

TECHNICAL FIELD

Described herein are abuse deterrent oral pharmaceutical compositions,methods for making the same, and methods of treatement using suchcompositions. In particular, oral pharmaceutical compositions thatmitigate the risk of overingestion of one or more active pharmaceuticalingredients are described.

BACKGROUND

Increased attention has been drawn to the recreational use and abuse ofprescription pharmaceutical compositions. The abuse, or non-medicinaluse, of prescription pharmaceutical compositions is an increasingproblem. Accordingly, preventing the abuse of prescriptionpharmaceuticals through the development of abuse deterrentpharmaceutical compositions has become a high public health priority forthe U.S. Food and Drug Administration (FDA). Prescription pharmaceuticalcompositions that are typically misused or abused fall, primarily, intothree groups: (1) opioids prescribed for pain; (2) Central NervousSystem (CNS) depressants prescribed for anxiety or sleep problems; and(3) stimulants, prescribed, for example, for attention deficithyperactivity, narcolepsy, or obesity.

Methods for abusing prescription pharmaceutical compositions are variedand can include, for example, extraction, boiling, melting,volatilization, physical tampering (e.g., grinding, grating, crushing,etc.), or direct administration. For purposes of abuse, methods ofadministering active drug substances obtained from prescriptionpharmaceutical compositions or of the pharmaceutical compositionsthemselves are similarly diverse and include, for example, injection,smoking, snorting, swallowing, sublingual or buccal administration,chewing, or administration as an anal or vaginal suppository.Alcohol-induced “dose dumping,” i.e., the rapid release of activepharmaceutical ingredients in the presence of a solvent such as ethanol,is also an abuse concern and safety issue. Other methods include rapidextraction under aqueous boiling conditions.

There are a number of strategies for preventing the abuse ofpharmaceuticals. Physical and chemical barriers can prevent theextraction of the drug or change the form of the drug making it lesslikely to be abused. Combinations of agonists and antagonists can beused, wherein the antagonist is only released upon product manipulationor tampering. Another strategy is to use aversive compounds that producean unpleasant effect when the dosage form is tampered with. In addition,prodrugs can be used, which are only changed into the active form of thedrug in the gastrointestinal tract. The pharmaceutical industry isutilizing these strategies to develop abuse-deterrent pharmaceuticalcompositions in order to reduce the potential for misuse of prescriptionpharmaceutical compositions.

There remains a need for abuse deterrent pharmaceutical compositionsthat comprise properties that mitigate the risk of accidental orintentional overingestion. In particular, there is a need forformulations that are resistant to active pharmaceutical ingredientextraction and that inhibit the risk of overingestion.

SUMMARY

One embodiment described herein is an oral immediate releasepharmaceutical composition comprising a dry mixture comprising one ormore active pharmaceutical ingredients (API), one or more sequesteringagents, and optionally, one or more pharmaceutically acceptableexcipients, where less than about 1% of the API is bound to thesequestering agent. In one aspect, upon ingestion of at least one doseby a subject, the sequestering agent adsorbs a quantity of the API andimpedes its absorption into the subject's systemic circulation. Inanother aspect, the quantity of the API adsorbed by the sequesteringagent is about 0.5% to about 15%. In another aspect, a greater quantityof API is adsorbed by the sequestering agent when a plurality of dosesof the composition are simultaneously ingested or successively ingestedover about a 4-hour period. In another aspect, the quantity of the APIadsorbed by the sequestering agent is about 15% to about 70%. In anotheraspect, the plurality of doses is 2 or greater. In another aspect, theplurality of doses is from 2 to 30. In another aspect, the compositionis capable of achieving one or more of the following pharmacokineticparameters: (a) a lower C_(max) for the API as compared to an equivalentAPI dose lacking a sequestering agent; (b) a delayed T_(max) for the APIas compared to an equivalent API dose lacking a sequestering agent; (c)a similar plasma AUC for the API as compared to an equivalent API doselacking a sequestering agent; (d) an extended absorption time for theAPI as compared to an equivalent API dose lacking a sequestering agent;or (e) an extended clearance time for the API as compared to anequivalent API dose lacking a sequestering agent. In another aspect, theAPI to sequestering agent comprises a mass ratio of about 1:2 to about1:8. In another aspect, the API to sequestering agent comprises a massratio of about 1:3 to about 1:5. In another aspect, the API tosequestering agent comprises a mass ratio of about 1:4. In anotheraspect, the API comprises an opioid. In another aspect, the APIcomprises hydrocodone, oxycodone, oxymorphone, hydromorphone, morphine,codeine, salts thereof, or combinations thereof. In another aspect, theAPI comprises hydrocodone bitartrate. In another aspect, thesequestering agent comprises one or more ion exchange polymers. Inanother aspect, the sequestering agent comprises one or more cationexhange polymers or salts thereof. In another aspect, the sequesteringagent comprises a sulfonated styrene and divinylbenzene copolymer or asalt thereof. In another aspect, the sequestering agent comprisespolystyrene sulfonate or a salt thereof. In another aspect, thecomposition comprises a dry admixture of hydrocodone bitartrate andsodium polystyrene sulfonate at a mass ratio of about 1:4. In anotheraspect, the composition is non-layered. In another aspect, thecomposition comprises: about 10% to about 30% API; and about70% to 90%sequestering agent. In another aspect, the composition comprises about20% API; and about 80% sequestering agent. In another aspect, thecomposition comprises about 20% hydrocodone bitartrate; and about 80%polystyrene sulfonate or a salt thereof. In another aspect, thecomposition is encapsulated in a capsule or formed as a tablet. Inanother aspect, the composition exhibits an in vitro disintegration ordissolution rate comprising about 50% disintegration or dissolutionafter about 1 minute to about 15 minutes at pH 1.2.

Another embodiment described herein is an oral immediate releasepharmaceutical composition comprising a dry mixture of hydrocodone or asalt thereof and polystyrene sulfonate or a salt thereof in a mass ratioof about 1:2 to about 1:8, where less than about 1% of the hydrocodoneis bound to the polystyrene sulfonate. In one aspect, upon ingestion ofat least one dose by a subject, the polystyrene sulfonate adsorbs aquantity of the hydrocodone and impedes its absorption into thesubject's systemic circulation. In another aspect, the quantity ofhydrocodone adsorbed by the polystyrene sulfonate is about 0.5% to about15%. In another aspect, a greater quantity of hydrocodone is adsorbed bythe polystyrene sulfonate when a plurality of doses of the compositionare simultaneously ingested or successively ingested over about a 4-hourperiod. In another aspect, the quantity of hydrocodone adsorbed by thepolystyrene sulfonate is about 15% to about 70%. In another aspect, theplurality of doses is 2 or greater. In another aspect, the plurality ofdoses is from 2 to 30. In another aspect, the composition is capable ofachieving one or more of the following pharmacokinetic parameters: (a) alower C_(max) for the hydrocodone as compared to an equivalenthydrocodone dose lacking polystyrene sulfonate t; (b) a delayed T_(max)for hydrocodone as compared to an equivalent hydrocodone dose lackingpolystyrene sulfonate; (c) a similar plasma AUC for hydrocodone ascompared to an equivalent hydrocodone dose lacking polystyrenesulfonate; (d) an extended absorption time for hydrocodone as comparedto an equivalent hydrocodone dose lacking polystyrene sulfonate; or (e)an extended clearance time for hydrocodone as compared to an equivalenthydrocodone dose lacking polystyrene sulfonate. In another aspect, thecomposition comprises a non-layered powder suspension. In anotheraspect, the mass ratio of hydrocodone to polystyrene sulfonate is about1:4. In another aspect, the composition exhibits an in vitrodisintegration or dissolution rate comprising about 50% disintegrationor dissolution after about 1 minute to about 15 minutes at pH 1.2.Another aspect is a dosage form comprising the foregoing compositiondescribed herein encapsulated in a capsule or formed as a tablet.

Another embodiment described herein is a method for treating pain whilemitigating the risk of overingestion, the method comprisingadministering to a subject in need thereof an oral immediate releasepharmaceutical composition comprising a dry mixture of one or moreactive pharmaceutical ingredients (API), one or more sequesteringagents, and optionally, one or more pharmaceutically acceptableexcipients, where less than 1% of the API is bound to the sequesteringagent, and following ingestion of at least one dose by a subject, thesequestering agent adsorbs a quantity of the API and impedes its releaseinto the subject's systemic circulation. In one aspect, the API tosequestering agent mass ratio is about 1:2 to about 1:8. In anotheraspect, the quantity of the API adsorbed by the sequestering agent isabout 0.5% to about 15%. In another aspect, a greater quantity of API isadsorbed by the sequestering agent when a plurality of doses of thecomposition are simultaneously ingested or successively ingested overabout a 4-hour period. In another aspect, the quantity of the APIadsorbed by the sequestering agent is about 15% to about 70%. In anotheraspect, the plurality of doses is 2 or greater. In another aspect, theplurality of doses is from 2 to 30. In another aspect, the compositionis capable of achieving one or more of the following pharmacokineticparameters: (a) a lower C_(max) for the API as compared to an equivalentAPI dose lacking a sequestering agent; (b) a delayed T_(max) for the APIas compared to an equivalent API dose lacking a sequestering agent; (c)a similar plasma AUC for the API as compared to an equivalent API doselacking a sequestering agent; or (d) an extended clearance time for theAPI as compared to an equivalent API dose lacking a sequestering agent.In another aspect, the API comprises hydrocodone, oxycodone,oxymorphone, hydromorphone, morphine, codeine, salts thereof, orcombinations thereof. In another aspect, the sequestering agentcomprises one or more ion exchange polymers. In another aspect, thecomposition comprises a dry powder suspension of hydrocodone bitartrateand sodium polystyrene sulfonate at a mass ratio of about 1:4. Inanother aspect, the composition is a non-layered. In another aspect, thecomposition comprises about 10% to about 30% API; and about70% to 90%sequestering agent. In another aspect, the composition comprises about20% API; and about 80% sequestering agent. In another aspect, thecomposition comprises about 20% hydrocodone bitartrate; and about 80%polystyrene sulfonate or a salt thereof. In another aspect, thecomposition is encapsulated in a capsule or formed as a tablet. Inanother aspect, the composition exhibits an in vitro disintegration ordissolution rate comprising about 50% disintegration or dissolutionafter about 1 minute to about 15 minutes at pH 1.2. In another aspect,the pain arises from one or more of diabetic neuropathy, chronicarthritis, osteoarthritis, rheumatoid arthritis, acute tendonitis,bursitis, headaches, migraines, chronic neuropathies, shingles,premenstrual symptoms, sports injuries, malignancy, radiculopathy,sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica, granulomaannulare, trauma, cancer, or a combination thereof.

Another embodiment described herein is method for mitigating the risk ofoveringestion, the method comprising administering to a subject in needthereof one or more oral immediate release pharmaceutical compositionscomprising one or more active pharmaceutical ingredients (API), one ormore sequestering agents, and optionally, one or more pharmaceuticallyacceptable excipients, where less than about 1% of the API is bound tothe sequestering agent, and following ingestion of at least one dose bya subject, the sequestering agent adsorbs a quantity of the API andimpedes its release into the subject's systemic circulation. In oneaspect, the API to sequestering agent mass ratio is about 1:2 to about1:8. In another aspect, the quantity of the API adsorbed by thesequestering agent is about 0.5% to about 15%. In another aspect, agreater quantity of API is adsorbed by the sequestering agent when aplurality of doses of the composition are simultaneously ingested orsuccessively ingested over about a 4-hour period. In another aspect, thequantity of the API adsorbed by the sequestering agent is about 15% toabout 70%. In another aspect, the plurality of doses is 2 or greater. Inanother aspect, the plurality of doses is from 2 to 30. In anotheraspect, the composition is capable of achieving one or more of thefollowing pharmacokinetic parameters: (a) a lower C_(max) for the API ascompared to an equivalent API dose lacking a sequestering agent; (b) adelayed T_(max) for the API as compared to an equivalent API doselacking a sequestering agent; (c) a similar plasma AUC for the API ascompared to an equivalent API dose lacking a sequestering agent; or (d)an extended clearance time for the API as compared to an equivalent APIdose lacking a sequestering agent. In another aspect, the API compriseshydrocodone, oxycodone, oxymorphone, hydromorphone, morphine, codeine,salts thereof, or combinations thereof. In another aspect, thesequestering agent comprises one or more ion exchange polymers. Inanother aspect, the composition comprises a dry powder suspension ofhydrocodone bitartrate and sodium polystyrene sulfonate at a mass ratioof about 1:4. In another aspect, the composition is a non-layered. Inanother aspect, the composition comprises about 10% to about 30% API;and about 70% to 90% sequestering agent. In another aspect, thecomposition comprises about 20% API; and about 80% sequestering agent.In another aspect, the composition comprises about 20% hydrocodonebitartrate; and about 80% polystyrene sulfonate or a salt thereof. Inanother aspect, the composition is encapsulated in a capsule or formedas a tablet. In another aspect, the composition exhibits an in vitrodisintegration or dissolution rate comprising about 50% disintegrationor dissolution after about 1 minute to about 15 minutes at pH 1.2.

Another embodiment described herein is a method for manufacturing anoveringestion-inhibiting pharmaceutical dosage form, the methodcomprising (i) combining one or more active pharmaceutical ingredients(API) with one or more sequestering agents, and optionally one or morepharmaceutically acceptable excipients to form a powder suspension; and(ii) forming a dosage form from the powder suspension. In one aspect,less than about 1% of the API is bound to the sequestering agent. Inanother aspect, the API to sequestering agent mass ratio is about 1:2 toabout 1:8. Another aspect is a dosage form produced by the manufacturingmethod described herein. In another aspect, the dosage form comprises anAPI comprising an opioid or a salt thereof and the sequestering agentcomprises an ion exchange resin or a salt thereof. In another aspect,the dosage form is a capsule or a tablet. In another aspect, the dosageform exhibits an in vitro disintegration or dissolution rate comprisingabout 50% disintegration or dissolution after about 1 minute to about 15minutes at pH 1.2.

Another embodiment described herein is a kit comprising one or moredosage forms comprising one or more oral immediate releasepharmaceutical composition comprising one or more active pharmaceuticalingredients (API), one or more sequestering agents, and optionally, oneor more pharmaceutically acceptable excipients, wherein less than about1% of the API is bound to the sequestering agent, and followingingestion of at least one dose by a subject, the sequestering agentadsorbs a quantity of the API and impedes its release into systemiccirculation; (b) one or more moisture proof dispensing receptacles; andoptionally (c) an insert comprising instructions, prescribinginformation, contraindications, or warnings.

Another embodiment described herein is a method for regulating theconcentration of an active pharmaceutical ingredient in a subject'ssystemic circulation, the method comprising administering to a subjectone or more oral immediate release pharmaceutical compositionscomprising one or more active pharmaceutical ingredients (API), one ormore sequestering agents, and optionally, one or more pharmaceuticallyacceptable excipients, where less than about 1% of the API is bound tothe sequestering agent, and following ingestion of at least one dose bya subject, the sequestering agent adsorbs a quantity of the API andimpedes its release into the subject's systemic circulation. In anotheraspect, the API to sequestering agent mass ratio is about 1:2 to about1:8. In another aspect, the quantity of the API adsorbed by thesequestering agent is about 0.5% to about 15%. In another aspect, agreater quantity of API is adsorbed by the sequestering agent when aplurality of doses of the composition are simultaneously ingested orsuccessively ingested over about a 4-hour period. In another aspect, thequantity of the API adsorbed by the sequestering agent is about 15% toabout 70%. In another aspect, the plurality of doses is 2 or greater. Inanother aspect, the plurality of doses is from 2 to 30. In anotheraspect, the composition is capable of achieving one or more of thefollowing pharmacokinetic parameters: (a) a lower C_(max) for the API ascompared to an equivalent API dose lacking a sequestering agent; (b) adelayed T_(max) for the API as compared to an equivalent API doselacking a sequestering agent; (c) a similar plasma AUC for the API ascompared to an equivalent API dose lacking a sequestering agent; or (d)an extended clearance time for the API as compared to an equivalent APIdose lacking a sequestering agent. In another aspect, the sequesteringagent comprises one or more ion exchange polymers. In another aspect,the composition is a non-layered. In another aspect, the compositioncomprises about 10% to about 30% API; and about 70% to 90% sequesteringagent. In another aspect, the composition comprises about 20% API; andabout 80% sequestering agent. In another aspect, the composition isencapsulated in a capsule or formed as a tablet. In another aspect, thecomposition exhibits an in vitro disintegration or dissolution ratecomprising about 50% disintegration or dissolution after about 1 minuteto about 15 minutes at pH 1.2. In another aspect, the method furthercomprises: (a) acquiring a bodily fluid from the subject; (b) measuringthe concentration of the API in the subject's circulation; and (c)according to the measured API concentration and a desired optimal APItherapeutic concentration, either: (i) administering one or more dosesof the composition comprising the API and a sequestering agent; (ii)administering an equivalent dose of the API comprising a compositionlacking a sequestering agent; or (iii) administering either one or moredoses of the composition comprising the API and a sequestering agent oradministering an equivalent dose of the API comprising a compositionlacking a sequestering agent after a period of about 30 min to about 12hours.

Another embodiment described herein is a pharmaceutical compositioncomprising an abuse deterrent controlled release composition comprisingone or more active pharmaceutical ingredients that prevent overingestion of abuse prone drugs. The composition is structured to preventextraction of the active pharmaceutical ingredients. The compositionformulations described herein minimize the likelihood of tampering,“dose dumping,” or the extraction of active pharmaceutical ingredientsfrom the composition. Further, the composition is structured to reducethe release of one or more active pharmaceutical ingredients whenmultiple pharmaceutical compositions are ingested.

One embodiment described herein is an abuse deterrent oralpharmaceutical composition comprising a tamper resistant controlledrelease composition, wherein the tamper resistant controlled releasecomposition comprises a means for preventing the crushing, grating,grinding, cutting, solvating, or dissolving of the tamper resistantcontrolled release composition comprising one or more activepharmaceutical ingredients. In one aspect, the abuse deterrent oralpharmaceutical composition comprises a means for preventing the overingestion of one or more active pharmaceutical ingredients when morethan the recommended dosage is taken.

Another embodiment described herein is an anti-overingestion abusedeterrent pharmaceutical composition comprising a soft capsule shellcomposition comprising a first one or more ionically charged polymers,wherein the soft capsule shell encapsulates a composition comprising oneor more active pharmaceutical ingredients and a second one or moreionically charged polymers, wherein the one or more activepharmaceutical ingredients is in a pH responsive resinate complex withthe second one or more ionically charged polymers. In one aspectdescribed herein, the soft capsule shells described herein comprise twoor more soft capsule shell sub compositions that comprise a total softcapsule shell composition, wherein the two or more soft capsule shellsub compositions are spatially separated. In another aspect, the one ormore ionically charged polymers comprises at least two ionically chargedpolymers. In another aspect, the total soft capsule shell compositioncomprises a first soft capsule shell sub composition and a second softcapsule shell sub composition. In another aspect, the at least twoionically charged polymers comprise at least one positively chargedpolymer and at least one negatively charged polymer. In another aspect,each one of the at least two ionically charged polymers are each in theat least two or more of the soft capsule shell sub compositions. Inanother aspect, the first soft capsule shell sub composition comprisesabout 1% to about 90% of the total soft capsule shell composition. Inanother aspect, the second soft capsule shell sub composition comprisesabout 1% to about 90% of the total soft capsule shell composition. Inanother aspect, the first soft capsule shell sub composition comprises apositively charged polymer. In another aspect, the second soft capsuleshell sub composition comprises a negatively charged polymer. In anotheraspect, the positively charged polymer comprises a dimethylaminoethylmethacrylate copolymer. In another aspect, the negatively chargedpolymer comprises a methacrylic acid copolymer. In another aspect, thepositively charged polymer comprises about 1% to about 25% of at leastone of the soft capsule shell sub compositions. In another aspect, thenegatively charged polymer comprises about 1% to about 25% of at leastone of the soft capsule shell sub compositions. In another aspect, thesoft capsule shell further comprises one or more adhesive polymers. Inanother aspect, the one or more adhesive polymers comprisespolycarbophil, xanthan gum, Carbopol® 1342P, Carbopol® 974P, chitosan,Carbopol® 971P, hydroxypropylmethyl cellulose (e.g., Methocel K100M orMethocel K15M), sodium carboxymethyl cellulose, hydroxypropylmethylcellulose (Methocel K15M), gelatin, or acacia gum, or a combinationthereof. In another aspect, the one or more adhesive polymers comprisesabout 0.5%-20% of the soft capsule shell. In another aspect, the softcapsule shell further comprises one or more thermoresponsive polymers.In another aspect, the one or more thermoresponsive polymers comprisespoly(N-isopropylacrylamide), amine terminatedpoly(N-isopropylacrylamide), carboxylic acid terminatedpoly(N-isopropylacrylamide), poly(N-isopropylacrylamide-co-methacrylicacid), or poly(N-isopropylacrylamide-co-methacrylic acid-co-octadecylacrylate), or a combination thereof. In another aspect, the soft capsuleshell composition further comprises one or more film forming polymers,one or more plasticizers, a solvent, and optionally, an alkalineneutralizing agent, an acidic neutralizing agent, a coloring agent, aflavoring or a pharmaceutical excipient. In another aspect, each of thesoft capsule shell sub compositions comprises: (a) about 20% to about36% by weight of at least one film-forming polymer; (b) about 1% toabout 25% by weight of one or more ionically charged polymers; (c) about1% to about 20% by weight of at least one plasticizer; (d) about 10% toabout 40% by weight of a solvent; (e) optionally about 1% to about 5% byweight of at least one alkali-neutralizing agent; (f) optionally about1% to about 5% by weight of at least one acidic neutralizing agent; (g)optionally about 1% to about 5% by weight of an opacifying agent; and(h) optionally about 0.05% to about 1% by weight of at least onecoloring agent. In another aspect, at least one of the soft capsuleshell sub compositions comprises: (a) about 30% by weight of at leastone film-forming polymer; (b) about 10% by weight of at least onenegatively charged polymer; (c) about 20% by weight of at least oneplasticizer; (d) about 1% by weight of at least one alkali-neutralizingagent; (e) about 37% by weight of a solvent; and (f) optionally about1.5% by weight of an opacifying agent; and (g) optionally about 0.05% toabout 1% by weight of at least one coloring agent. In another aspect, atleast one of the soft capsule shell sub compositions comprises: (a)about 25% by weight of at least one film-forming polymer; (b) about 12%by weight of at least one positively charged polymer; (c) about 17% byweight of at least one plasticizer; (d) about 1% by weight of at leastone acidic neutralizing agent; (e) about 44% by weight of a solvent; and(f) optionally about 1.5% by weight of an opacifying agent; and (g)optionally about 0.05% to about 1% by weight of at least one coloringagent. In another aspect, the at least one soft capsule shell subcomposition comprises gelatin, acrylic methacrylate copolymers,glycerol, triethyl citrate, ammonia, water, and optionally titaniumdioxide. In another aspect, the at least one soft capsule shell subcomposition comprises gelatin, dimethylaminoethyl methacrylatecopolymer, glycerol, hydrochloric acid, water, and optionally titaniumdioxide. In another aspect, the composition comprises one or more activepharmaceutical ingredients and one or more ionically charged polymers,wherein the one or more active pharmaceutical ingredients is in a pHresponsive resinate complex with the one or more ionically chargedpolymers. In another aspect, the pH responsive resinate complexcomprises one or more positively charged polymers or one or morenegatively charged polymers or a combination of positively or negativelycharged polymers thereof. In another aspect, the pH responsive resinatecomplex comprises a cation exchange resin or an anion exchange resin ora combination thereof. In another aspect, the cation exchange resin oranion exchange resin comprises an average particle size of about 1 μm toabout 500 μm. In another aspect, the cation exchange resin or anionexchange resin comprises an ion exchange capacity of about 1 meq/g toabout 6 meq/g. In another aspect, the cation exchange resin comprises aweak cation exchange resin or a strong cation exchange resin. In anotheraspect, the cation exchange resin comprises a polymer based on repeatingalkyl or heteroalkyl units that may be optionally crosslinked andcomprise functional groups comprising a sodium polystyrene sulfonate ora carboxylic acid group. In another aspect, the cation exchange resincomprises Amberlite™ IRP 69 or Amberlite™ IRP 88 or a combinationthereof. In another aspect, the anion exchange resin comprises a polymerbased on repeating branched or unbranched alkyl or heteroalkyl unitsthat may be optionally crosslinked comprising functional groupscomprising a primary amine or a quaternary ammonium. In another aspect,the one or more active pharmaceutical ingredients is positively chargedor negatively charged and forms a complex with the cation exchange resinor anion exchange resin based upon an intermolecular ionic interactionwith the one or more ionically charged polymers. In another aspect, theone or more active pharmaceutical ingredients is in complex with theresinate complex at a normal pH and disassociates from the resinatecomplex at a pH range found in the stomach. In another aspect, thecomposition further comprises one or more adhesive polymers. In anotheraspect, the one or more adhesive polymers comprises polycarbophil,xanthan gum, Carbopol® 1342P, Carbopol® 974P, chitosan, Carbopol® 971P,hydroxypropylmethyl cellulose (e.g., Methocel K100M or Methocel K15M),sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose (MethocelK15M), gelatin, or acacia gum, or a combination thereof. In anotheraspect, the one or more adhesive polymers comprises polycarbophil. Inanother aspect, the composition further comprises: (a) a liquid lipidvehicle; (b) a semi solid lipid or lipophilic vehicle; (c) at least oneionic hydrophilic polymer; (d) at least one hydroscopic polymer; and (e)a suspension agent; and (f) optionally a non-ionic surfactant; and (g)optionally a pH-buffering agent In another aspect, the compositioncomprises: (a) soybean oil; (b) polyethylene glycol glyceride ester; (c)bee's wax; (d) polyvinylpyrrolidone or polyethylene oxide; (e) carbomerpolymer; (g) dimethylaminoethyl methacrylate copolymer; (g) fumedsilica; and (h) optionally a poloxamer non-ionic surfactant; and (I)optionally N-methyl-D-glucamine. In another aspect, the compositioncomprises: (a) about 45% to about 52% soybean oil; (b) about 1.5% toabout 5% Gelucire® 43/01; (c) about 1.8% to about 4% bee's wax; (d)about 2% to about 8% Kollidon® 90 F; (e) about 0.5% to about 4%Carbopol® 971 A; (f) about 2% to about 8% EUDRAGIT® EPO; (g) about 0.5%to about 5% Aerosil 200; and (h) optionally about 1% to about 10%Pluronic® F127; and (i) optionally about 0.5% to about 6%N-methyl-D-glucamine. In another aspect, the composition furthercomprises: (a) one or more hydrophilic vehicles; (b) at least onecarbomer polymers; (c) at least one hydroscopic polymer; (c) at leastone hydrophilic polymer; (d) at least one ion exchange resin. In anotheraspect, the composition comprises: (a) polyethylene glycol 600 (b)polyethylene glycol 1000; (b) carbopol® 974P; (c) polyvinylpyrrolidone;(c) hydroxypropylmethyl cellulose; and (d) at least one cation exchangeresin. In another aspect, the composition comprises: (a) about 40% toabout 70% polyethylene glycol 600 (b) about 2% to about 15% polyethyleneglycol 1000; (b) about 0.25% to about 3% carbopol® 974P; (c) about 2% toabout 20% polyvinylpyrrolidone K90; (c) about 2% to about 20%hydroxypropylmethyl cellulose K100M; and (d) about 1% to about 20% of atleast one cation exchange resins in complex with one or more activepharmaceutical ingredients. In another aspect, the at least one cationexchange resin comprises Amberlite™ IRP 69 or Amberlite™ IRP 88 or acombination thereof. In another aspect, the pharmaceutical compositionfurther comprises a means for having gastro-retentive properties. Inanother aspect, the means for having gastro-retentive propertiescomprises a means for floating the pharmaceutical composition in agastric compartment. In another aspect, the means for floating thepharmaceutical composition in a gastric compartment comprises theinclusion of one or more of an effervescent gas generating system, acolloidal gel barrier, porous beads, a microporous membrane, or theinclusion of one or more low-density excipients to the pharmaceuticalcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Illustration of the anti-overingestion properties of thepharmaceutical compositions.

FIG. 2. Illustration of an exemplary anti-overingestion pharmaceuticalcomposition.

FIG. 3. In vitro drug release of an Amberlite™ IRP69-dextromethorphandrug resinate at pH 1.5, pH 4.8, and pH 7.4 buffers USP Apparatus I.

FIG. 4. In vitro drug release of an Amberlite™ IRP88-dextromethorphandrug resinate at pH 1.5, pH 4.8, and pH 7.4 buffers using USP ApparatusI.

FIG. 5. In vitro drug release of an Amberlite™ IRP88 or Amberlite™IRP69-dextromethorphan drug resinate in distilled water using USPApparatus I.

FIG. 6. In vitro drug release of an Amberlite™ IRP88 or Amberlite™IRP69-dextromethorphan drug resinate in boiling distilled water.

FIG. 7. In vitro drug release of an Amberlite™ IRP88 or Amberlite™IRP69-dextromethorphan drug resinate in boiling distilled water.

FIG. 8. In vitro drug release of an Amberlite™ IRP69-dextromethorphandrug resinate in simulated gastric fluid, pH 1.2 using USP Apparatus I.

FIG. 9. In vitro drug release of an Amberlite™ IRP88-dextromethorphandrug resinate in simulated gastric fluid, pH 1.2 using USP Apparatus I.

FIG. 10. In vitro drug release of an Amberlite™ IRP69-dextromethorphandrug resinate when either 1, 5, or 10 capsules were dissolved togetherin 0.1 N HCl using USP Apparatus II.

FIG. 11. In vitro drug release of dextromethorphan from control hardcapsule shells (without resinate) when either 1 or 10 capsules weredissolved together in 0.1 N HCl using USP Apparatus II.

FIG. 12. In vitro drug release of an Amberlite™ IRP88-dextromethorphandrug physical blend when either 1 or 10 capsules were dissolved togetherin 0.1 N HCl using USP Apparatus II.

FIG. 13. In vitro drug release of an Amberlite™ IRP69-dextromethorphandrug physical blend when either 1 or 10 capsules were dissolved togetherin 0.1 N HCl using USP Apparatus II.

FIG. 14. In vitro drug release of an Amberlite™ IRP69- or Amberlite™IRP88-dextromethorphan drug resinate when either 1, 5 or 10 capsuleswere dissolved together in 0.1 N HCl using USP Apparatus II with mediarenewal every 15 minutes.

FIG. 15. In vitro drug release of Amberlite™ IRP88-dextromethorphan drugresinates in a hydrogel abuse deterrent composition according to thecomposition of Table 14 (−PCP) and Table 16 (+PCP) when either 1 or 5capsules were dissolved together according to the parameters of Table12.

FIG. 16. In vitro drug release of Amberlite™ IRP69-dextromethorphan drugresinates in a hydrogel abuse deterrent composition according to thecomposition of Table 14 (−PCP) and Table 16 (+PCP) when either 1 or 5capsules were dissolved together according to the parameters of Table12.

FIG. 17. In vitro drug release of Amberlite™ IRP69-dextromethorphan drugphysical blend in a hydrogel abuse deterrent composition according tothe composition of Table 14 when either 1 or 5 capsules were dissolvedtogether or when 5 control dextromethorphan API-only containingcompositions were dissolved according to the parameters of Table 12.

FIG. 18. Pharmacokinetic results from hydrocodone formulations in maledogs. Average plasma concentration of hydrocodone as a function of timefor the Test and Control dosage forms at shown in Tables 19-20.

FIG. 19. Pharmacokinetic results from hydrocodone formulations in maledogs. (A) C_(max) versus dose for 5 mg, 25 mg, and 50 mg doses. (B)C_(max)/dose for the same data in A.

FIG. 20. Pharmacokinetic results from hydrocodone formulations in maledogs. (A) AUC_(0-14 hr) versus dose for 5 mg, 25 mg, and 50 mg doses.(B) AUC_(0-14 hr)/dose for the same data in A.

DETAILED DESCRIPTION

Described herein are abuse deterrent pharmaceutical compositions thatcan abrogate oral overingestion of large quantities of activepharmaceutical ingredients accidentally or purposely imbibed by asubject. The pharmaceutical compositions described herein provide abusedeterrent compositions and methods for preparation thereof. Thecompositions can be solids or liquids and delivered as tablets, hardcapsules, soft capsules, or enteric dosage forms.

The term “abuse deterrent,” or “tamper resistant” as used herein, refersto a pharmaceutical composition that is resistant to tampering oraccessing the active pharmaceutical ingredient for recreational drug useor drug abuse. The term abuse deterrent further encompasses the term“anti-overingestion.”

The term “anti-overingestion” refers to the prevention or mitigation oforal over ingesting greater than one dose of an active pharmaceuticalingredient when multiple dosage forms are taken simultaneously or insuccession prior to gastric emptying, so that high levels of the drugare systemically absorbed. As used herein, anti-overingestion canmitigate both oral abuse of an active pharmaceutical agent for itseuphoric or dissociative effects, or alternatively mitigate intentionalor accidental overdose that could lead to adverse health effects such asdepressed respiration, comma, cardiac arrest, or death.

The phrase “recreational drug use,” as used herein, refers to thevoluntary use of an active pharmacetical agent or drug for a non-medicalpurpose to induce an effect, such as pleasure, satisfaction, euphoria,dissociation, or to enhance an experience.

The term “drug abuse,” as use herein, refers to the habitual,compulsive, or recurrent use of an active pharmaceutical agent or drug,often despite negative consequences.

The phrases “oral abuse” or “oral drug abuse” refer to the intentionalor accidental oral ingestion of greater than the prescribed orrecommended dose of an active pharmaceutical agent by ingesting multipledosage forms simultaneously or successively over a period of time. Oralabuse as used herein is distinguished from other abusive administrationroutes such as insufflation, injection, or ingestion of an extracted ortampered active pharmaceutical ingredient. Oral abuse is difficult tocounteract or prevent because abuse is predicated on multiple dosageforms being ingested through the normal or appropriate route ofadministration.

The term “tampering,” as used herein, refers to any kind of actual orattempted physical manipulation or interference that may result inparticle size reduction of a pharmaceutical composition. Tampering, asused herein also includes any actual or attempted dissolution orextraction of active pharmaceutical ingredients using solvents.Compositions that are resistant to physical tampering are formulated insuch a way that the composition cannot readily reduced to a form that issuitable for abuse, such as, for example, injection or snorting, becausethe tablet cannot easily be ground, grated, dissolved, extracted, andthe like at any temperature. Examples of physical tampering include, butare not limited to, crushing, grinding, grating, cutting, crisping, andother methods of particle size reduction. Dissolution tampering includesactual or attempted actions to dissolve or extract active pharmaceuticalingredients using aqueous or organic solvents such as water, ethanol,isopropanol, ethyl acetate, acetone, ether, or the like, at anytemperature including boiling. Tampering, as used herein, includes “dosedumping.”

The term “dose dumping” or “dumping” as used herein refers to the rapidrelease of the entire amount or a significant fraction of an activepharmaceutical ingredient or drug. Drug abusers often intentionallypursue dumping of a drug from the dosage form.

The terms “drug”, “active ingredient,” “active pharmaceuticalingredient,” or “active pharmaceutical agent” as used herein refer to anagent, active ingredient, compound, or substance, compositions, ormixtures thereof, that provide a pharmacological, often beneficial,effect. Reference to a specific active ingredient includes, whereappropriate, the active ingredient and any of its pharmaceuticallyacceptable salts or esters.

The terms “dosage” or “dose” denote any form of the active ingredientformulation that contains an amount sufficient to produce a therapeuticeffect with a single administration. The dosage form used herein is fororal administration. The preferred oral dosage forms are soft capsulesor enteric soft capsules.

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refers to the quantity (mass) of the active pharmaceuticalingredient comprised in a single soft capsule fill.

The term “formulation” or “composition” as used herein refers to theactive pharmaceutical ingredient or drug in combination withpharmaceutically acceptable excipients. This includes orallyadministrable formulations as well as formulations administrable byother means.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “controlled release” as used herein refers to a compositionthat does not immediately releases an active ingredient. “Controlledrelase” as used herein encompasses the terms “modified release,”“sustained release,” “extended release,” and “delayed release.”

The term “immediate release” as used herein refers to a composition thatreleases an active ingredient over a short period under physiologicalconditions or in an in vitro test.

The term “delayed” release” as used herein refers to a composition thatreleases an active ingredient after a period of time, for exampleminutes or hours, such that the active ingredient is not releasedinitially. A delayed release composition may provide, for example, therelease of a drug or active ingredient from a dosage form, after acertain period, under physiological conditions or in an in vitro test.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The terms “extended release” or “sustained release” as used hereinrefers to a composition that releases an active ingredient according toa desired profile over an extended period under physiological conditionsor in an in vitro test. By “extended period” it is meant a continuousperiod of time of at least about 1 hour; about 2 hours; about 4 hours;about 6 hours; about 8 hours; about 10 hours; about 12 hours; about 14hours; about 16 hours; about 18 hours; about 20 hours about 24 hours; oreven longer; specifically, over a period of about 18 hours underphysiological conditions or in an in vitro assay.

As used herein, the phrase “abuse deterrent controlled release” refersto a pharmaceutical composition comprising components or a formulationthat prevents liberation of the active pharmaceutical ingredient(s) fromthe composition for potential abuse or dose dumping and the compositionprovides controlled release delivery of the active pharmaceuticalingredient upon ingestion of the composition by a subject.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∝)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “AUC_(overall)” as used herein refers to the combined areaunder the blood (plasma, serum, or whole blood) concentration versustime curve, and is expressed in units of h·mg/L (or h·ng/mL) for atleast one or more doses of the pharmaceutical compositions describedherein. In one aspect, the “AUC_(overall)” refers to the combined areaunder the blood concentration versus time curve for at least two dosesof the pharmaceutical compositions described herein.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

As used herein, all percentages (%) refer to weight (mass) percentunless noted otherwise.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “has,” or“having,” and the like, mean “comprising.”

The term “or” can be conjunctive or disjunctive.

Described herein are pharmaceutical compositions comprising abusedeterrent controlled release matrices comprising active pharmaceuticalingredients. The capsule shell and matrix is structured to preventextraction and over ingestion of the active pharmaceutical ingredients.

In one embodiment, the pharmaceutical composition described hereincomprises a soft capsule comprising an abuse deterrent controlledrelease matrix comprising an active pharmaceutical ingredient. In oneembodiment, the active pharmaceutical ingredient is an analgesic. Inanother embodiment, the active pharmaceutical ingredient is an opioidanalgesic.

In another embodiment, the soft capsule comprising a matrix can providecontrolled release properties. Such controlled release matrix fills aredescribed in International Patent Application Publication No. WO2005/009409 and WO 2006/096580, U.S. Patent Application Publication Nos.US 2006/0115527 and US 2007/0053868, and U.S. Pat. Nos. 8,293,270 and8,333,989, each of which are incorporated by reference herein for suchteachings. In one aspect, the soft capsule and matrix can be configuredto provide controlled release, extended release, sustained release,delayed release, or combinations thereof.

In other embodiments, the pharmaceutical composition described hereincomprises abuse deterrent properties. These abuse deterrent propertiesreduce the likelihood that the active pharmaceutical ingredient can beextracted from the composition through mechanisms, including but notlimited to crushing, grating, grinding, or cutting of the capsule toexpose the matrix thereby facilitating solvation or extraction of theactive pharmaceutical ingredient. Exemplary and non-limiting abusedeterrent matrices useful in the pharmaceutical composition describedherein may be those found in PCT International Application No.PCT/US2015/024464 and in U.S. patent application Ser. No. 14/679,233,each of which is incorporated by reference herein in their entirety. Inaddition, the abuse deterrent properties reduce the likelihood that theactive pharmaceutical ingredient can be extracted from the compositionby dissolving or extracting in ethanol solutions of about 1% to about50%, dissolving in solutions having pH values from about 1 to about 12,or dissolving in household chemical compositions, including water,coffee, vinegar, cola, milk, ethanol, isopropanol, acetone, ethylacetate, or other common solvents. In addition, the abuse deterrentproperties further reduce the likelihood that the active pharmaceuticalingredient can be extracted by boiling in water or ethanol solutions.

In other embodiments described herein, the composition comprises a lipidor lipophilic vehicle that provides a suspension or a solution of theactive pharmaceutical ingredient. In one aspect, a soft capsulecomprising an active pharmaceutical ingredient provides controlledrelease of the active pharmaceutical ingredient.

In other embodiments described herein, the pharmaceutical compositionprovides matrix fills for the active pharmaceutical ingredient, orderivatives thereof, based on lipids or lipophilic materials. Thematrices described herein have a hydrophobic (lipophilic) surface incontact with a hydrophilic soft capsule shell to minimize any potentialshell-fill interactions, such as when the soft capsules are filled withhydrophilic materials. In one embodiment described herein are methodsfor manufacturing matrix fills comprising an abuse deterrent controlledrelease composition comprising an active pharmaceutical ingredient in asoft capsule in the form of a suspension, where part or all of theactive pharmaceutical ingredient is suspended within the matrix. In oneembodiment described herein is a soft capsule having a shell and anabuse deterrent controlled release matrix fill, wherein the matrixincludes an active pharmaceutical ingredient suspended as solidparticles within the lipophilic vehicle.

In one embodiment described herein is a soft or hard capsule having oneor more active pharmaceutical ingredients in a resinate complex with oneor more ion exchange resins described herein. In one aspect describedherein, the one or more active pharmaceutical ingredients may be blendedwith one or more ion exchange resins described herein.

In one embodiment described herein, an exemplary abuse deterrentcontrolled release matrix has the composition of Table 1 and Table 2,including all possible iterations of the specified ranges that provide100% for the total weight percentage, including or excluding theoptional colorings, flavorings, or pharmaceutically acceptableexcipients.

TABLE 1 Exemplary Abuse Deterrent Controlled Release CompositionComponent Exemplary Components Composition Range (%) Lipid or lipophilicLiquid lipid vehicle (LLV) and/or Semisolid  31-92 vehicle(s) lipidvehicle (SLV): soybean oil, bee's wax (LLV: 25-60/SLV: 6-32) Non-ionicsurfactant(s) Pluronic ® F127, poloxamer, Tween ® 80,   1-15 Triton ™ XHygroscopic polymer(s) Polyvinylpyrrolidone (copovidone), ethyl   1-10cellulose, hydroxyproply methylcellulose, polyethylene oxide Hydrophilicionic Carbopol, Eudragit ®, Ethylenediamine   2-20 polymer(s) Suspensionagent(s) Fumed silica, Aerosil ® 0.5-5 pH buffering agent(s)Triethanolamine, N-methyl-D-glucamine,   1-8 Tromethamine Activepharmaceutical Oxycodone, Tapentadol, Amytal,   5-50 ingredient withResin Dextromethorphan Exchange Resin Amberlite ™ IRP 69, Amberlite ™IRP 88,

TABLE 2 Exemplary Abuse Deterrent Controlled Release CompositionComposition Range Component Exemplary Components (%) Hydrophilic vehiclePolyethylene glycol 400-1000  40-80 Hygroscopic polymerPolyvinylpyrrolidone (copovidone), 0.5-10 polyethylene oxide Hydrophilicpolymer(s) Polyvinylpyrrolidone (copovidone),   1-10 ethyl cellulose,hydroxyproply methylcellulose (Methocel ™ K100M), polyethylene oxideActive pharmaceutical Oxycodone, Tapentadol, Amytal   5-50 ingredient(s)Exchange Resin Amberlite ™ IRP 69, Amberlite ™ IRP 88,

In another embodiment, the lipid or lipophilic vehicle can be a liquidlipophilic vehicle, a semisolid lipophilic vehicle, or combinationsthereof. Suitable lipid or lipophilic vehicles include mineral oil;light mineral oil; natural oils (e.g., vegetable, corn, canola,sunflower, soybean, olive, coconut, cocoa, peanut, almond, cottonseed,persic, sesame, squalane, castor, cod liver, etc) hydrogenated vegetableoil; partially hydrogenated oils; bee's wax (beeswax); polyethoxylatedbee's wax; paraffin; normal waxes; medium chain medium chainmonoglycerides, diglycerides and triglycerides; higher aliphaticalcohols; higher aliphatic acids; long chain fatty acids; saturated orunsaturated fatty acids; hydrogenated fatty acids; fatty acidglycerides; polyoxyethylated oleic glycerides; monoglycerides anddiglycerides; mono-, bi- or tri-substituted glycerides; glycerolmono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate;propylene glycol dicaprylate; propylene glycol monolaurate; glycerylpalmitostearate; glyceryl behenate; diethyleneglycol palmitostearate;polyethyleneglycol stearate; polyoxyethyleneglycol palmitostearate;glyceryl mono palmitostearate; cetyl palmitate; polyethyleneglycolpalmitostearate; dimethylpolysiloxane; mono- or di-glyceryl behenate;fatty alcohols associated with polyethoxylate fatty alcohols; cetylalcohol; octyl dodecanol; myristyl alcohol; isopropyl myristate,isopropyl palmitate, stearic acid, stearyl alcohol, and others known inthe art.

In one embodiment, the lipid or lipophilic vehicle comprises both aliquid lipophilic vehicle and a semisolid lipophilic vehicle. In oneembodiment, the liquid lipid or lipophilic vehicle can be olive oil,soybean oil, sunflower oil, canola oil, palmitoleic acid, oleic acid,myristoleic acid, linoleic acid, arachidonic acid, paraffin oil, ormineral oil. In another embodiment, the semi-solid lipophilic vehiclecan be a polyethylene glycol glyceride ester, paraffin wax, carnaubawax, or bee's wax. In another embodiment, the semi-solid lipophilicvehicle can be Gelucire® 33/01, Gelucire® 37/02, Gelucire® 39/01,Gelucire® 43/01, Gelucire® 44/14, Gelucire® 50/02, Gelucire® 50/13,Gelucire® 53/10, or Gelucire® 62/02. In another embodiment, theGelucire® semisolid lipid vehicle has a HLB value of about 1 and amelting point of about 43. In one aspect, the liquid lipid or lipophilicvehicle is soybean oil. In another aspect, the semisolid lipid orlipophilic vehicle comprises a wax. In another aspect, the semisolidlipid or lipophilic vehicle comprises bee's wax. In another aspect, thesemisolid lipid or lipophilic vehicle comprises carnauba wax. In anotheraspect, the semisolid lipid or lipophilic vehicle comprises a mixture ofbee's wax and carnauba wax.

In one embodiment, the composition comprises a surfactant. Thesurfactant can have a hydrophilic/lipophilic balance (HLB) value betweenabout 1 and about 25 and a melting point between about 25° C. and about70° C. The HLB characteristic of surfactants can be determined inaccordance with “Physical Pharmacy: Physical Chemical Principles in thePharmaceutical Sciences,” Fourth Edition, pp. 371-373, A. Martin, Ed.,Lippincott Williams & Wilkins, Philadelphia (1993). Suitable surfactantsinclude: glyceryl monocaprylate (e.g., Capmul® MCM), Pluronic® 10R5,Pluronic® 17R2, Pluronic® 17R4, Pluronic® 25R2, Pluronic® 25R4,Pluronic® 31R1, Pluronic® F 108, Pluronic® F 108 NF, Pluronic® F 108,Pluronic® F 108NF, Poloxamer 338, Pluronic® F 127, Pluronic® F 127 NF,Pluronic® F 127 NF 500 BHT Prill, Pluronic® F 127 NF Prill, Poloxamer407, Pluronic® F 38, Pluronic® F 38 Pastille, Pluronic® F 68, Pluronic®F 68 LF Pastille, Pluronic® F 68 NF, Pluronic® F 68 NF Prill, Poloxamer188, Pluronic® F 68 Pastille, Pluronic® F 77, Pluronic® F 77Micropastille, Pluronic® F 87, Pluronic® F 87 NF, Pluronic® F 87 NFPrill, Poloxamer 237, Pluronic® F 88, Pluronic® F 88 Pastille, Pluronic®F 98, Pluronic® L 10, Pluronic® L 101, Pluronic® L 121, Pluronic® L 31,Pluronic® L 35, Pluronic® L 43, Pluronic® L 61, Pluronic® L 62,Pluronic® L 62 LF, Pluronic® L 62D, Pluronic® L 64, Pluronic® L 81,Pluronic® L 92, Pluronic® N 3, Pluronic® P 103, Pluronic® P 104,Pluronic® P 105, Pluronic® P 123 Surfactant, Pluronic® P 65, Pluronic® P84, Pluronic® P 85, Adogen® 464, Alkanol® 6112, Brij® 52, Brij® 93,Brij® S2, Brij® S, Brij® 58, Brij® C10, Brij® L4, Brij® O10, Brij® O10,BRIJ® O20, Brij® S10, Brij® S20, ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol, ethylenediaminetetrakis(propoxylate-block-ethoxylate) tetrol, IGEPAL® CA-210, IGEPAL®CA-520, IGEPAL® CA-720, IGEPAL® CO-520, IGEPAL® CO-630, IGEPAL® CO-720,IGEPAL® CO-890, IGEPAL® DM-970, MERPOL® DA, MERPOL® HCS, MERPOL® OJ,MERPOL® SE, MERPOL® SH, MERPOL® A, Poly(ethylene glycol) sorbitantetraoleate, poly(ethylene glycol) sorbitol hexaoleate, poly(ethyleneglycol) (12), poly(ethylene glycol) (18),polyethylene-block-poly(ethylene glycol), sorbitan monopalmitate,2,4,7,9-tetramethyl-5-decyne-4,7-diol ethoxylate, Nonidet™ P-40, Triton™N-101, Triton™ X-100, Triton™ X-114, Triton™ X-405, TWEEN® 20, TWEEN®40, TWEEN® 60, TWEEN® 85, Zonyl® FS-300, or Zonyl® FSN. In oneembodiment, the surfactant comprises Pluronic® F127, Tween® 80, Span®80, IGEPAL®, Triton™ X-100, or Capmul® MCM.

In another embodiment, the abuse deterrent composition comprises one ormore hydrophilic polymers. Suitable, non-limiting hydrophilic polymerscomprise methylcellulose, hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,hydroxymethyl cellulose, polymethylmethacrylate,polyhydroxyethylmethacrylate, polyvinyl pyrrolidone,polyvinylpyrrolidone, copovidone, polyethylene oxide such as POLYOX™100,000-8,000,000 MW, polyvinyl alcohol, a copolymer ofpolyvinylpyrrolidone and polyvinyl acetate, or combinations thereof. Inone aspect, the hydrophilic polymers comprise one or more of Methocel™K100 Premium LV CR, K4M Premium CR, K15M Premium CR, K100 Premium CR,E4M Premium CR, E10M Premium CR, or E4M Premium (Dow Chemical Co.);POLYOX™, CELLOSIZE™, or WALOCEL™ CRT. Without being bound by any theory,it is thought that water coming into contact with the hydrophilicpolymer, such as methylcellulose or hydroxypropylmethylcellulose, causesit to expand or swell and further impede the release of activepharmaceutical ingredients from the composition. In one aspect, thehydrophilic polymer comprises methylcellulose. In one aspect, thehydrophilic polymer comprises hydroxypropylmethylcellulose. In anotheraspect, the hydrophilic polymer comprises a viscosity of about 10 cP toabout 100,000 cP. In another aspect, hydrophilic polymer comprises aviscosity of about 50 cP, about 100 cP, about 200 cP, about 300 cP,about 400 cP, about 500 cP, about 750 cP, about 1,000 cP, about 1,500cP, about 2,000 cP, about 2,500 cP, about 3,000 cP, about 3,500 cP,about 4,000 cP, about 4,500 cP, about 5,000 cP, about 6,000 cP, about7,000 cP, about 8,000 cP, about 9,000 cP, or about 10,000 cP, about15,000 cP, about 20,000 cP, about 30,000 cP, about 40,000 cP, about50,000 cP, about 60,000 cP, about 70,000 cP, about 80,000 cP, about90,000 cP, about 100,000 cP, greater than 100,000 cP, or even greater.In one aspect, methylcellulose has a viscosity of about 4,000 cP (e.g.,Methocel™ A4M). In another aspect, hydroxypropylmethylcellulose has aviscosity of about 100,000 cP (e.g., Methocel™ K100M).

In one embodiment, the composition comprises a hydrophilic ionicpolymer. In one embodiment, the hydrophilic polymers comprisepolyhydroxylalkylenediamine, dimethylaminoethyl methacrylate copolymer,Poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-(2-dimethylaminoethyl) 1:2:1 (Eudragit® EPO); sodiumcarboxy methylcellulose, carboxymethyl cellulose ethylenediamine, sodiumalginate, alginic acid, pectin, carbomers, Carbopol® copolymers(polyacrylic acid polymers), such as Carbopol® 934, Carbopol® 940,Carbopol® 941 or Carbopol® 974P; a Pemulen® polymer; polycarbophil polygalacturonic acid, polyglucoronic acid, chondroitic sulfate,carrageenan, and acrylic methacrylate copolymers. In one aspect, thehydrophilic polymer swells in aqueous media. In another aspect, thehydrophilic polymers swell at a pH of about 4 to about 6. In anotherembodiment, one or more hydrophilic ionic polymers form ionicinteractions. In another embodiment, the composition comprises anionicpolymers, cationic polymers, or mixtures thereof. In another embodiment,a hydrophilic cationic polymer and a hydrophilic anionic polymer arecombined to form an ionic polymer complex or network. In one aspect, thehydrophilic ionic polymer is Carbopol® 971A. In another aspect, thehydrophilic ionic polymer is Eudragit® EPO.

In another embodiment, the composition comprises a hygroscopic polymer.In one embodiment, the hygroscopic polymers includepolyvinylpyrrolidone, copovidone, hydroxypropylmethylcellulose,hydroxypropylcellulose, ethyl cellulose, methylcellulose, andpolyethylene oxide. Suitable hygroscopic polymers include polyvinylalcohol, a copolymer of polyvinylpyrrolidone and polyvinyl acetate,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, such asPOLYOX™ 100,000-600,000 MW, acacia, dextrin, starch,polyhydroxyethylmethacrylate, a water-soluble non-ionic polymethacrylateor copolymer thereof, a modified cellulose, a modified polysaccharide, anon-ionic gum, or a non-ionic polysaccharide. In one aspect, thehygroscopic polymer is polyvinylpyrrolidone. In one aspect, thehygroscopic polymer comprises Kollidon® 90 F. In one aspect, thehygroscopic polymer comprises a cellulose polymer. In one aspect, thehygroscopic polymer comprises hydroxypropylmethylcellulose (e.g., HPMC4M). In another aspect, the hygroscopic polymer is a polyethylene oxidepolymer (e.g., POLYOX™ 100,000).

In another embodiment, the abuse deterrent composition comprises one ormore hydrophilic vehicles. Suitable, non-limiting hydrophilic vehiclescomprise hydro-alcohols including propylene glycol, or polyethyleneglycols of a molecular weight ranging from about 200 to about 8,000(M_(N), number average molecular weight) or a mixture or combinationthereof. In one aspect, the hydrophilic vehicle comprises polyethyleneglycol. In another aspect, the hydrophilic vehicle comprisespolyethylene glycol 600. In another aspect, the hydrophilic vehiclecomprises polyethylene glycol 1000. In another aspect, the hydrophilicvehicle comprises polyethylene glycol 600 and polyethylene glycol 1000.

In one embodiment described herein, the composition comprises: (a) about35% to about 70% by mass of one or more flowability enhancers; (b) about20% to about 50% by mass of one or more release modifiers; and (c) about1% to about 30% by mass of one or more active pharmaceuticalingredients. In one aspect, the composition further comprises: (d) about0.05% to about 0.5% of one or more antioxidants. In one aspect, thecomposition comprises: (a) glyceryl monolinoleate; (b) polyethyleneoxide; and (c) an opiod such as oxycodone, hydrocodone, or saltsthereof. In another aspect, the composition further comprises: (d)butylated hydroxytoluene (BHT); and (e) butylated hydroxyanisole (BHA).In another aspect, the composition comprises: (a) about 50% to about 70%by mass of glyceryl monolinoleate; (b) about 25% to about 40% by mass ofpolyethylene oxide; and (c) about 1% to about 20% by mass of an opiodsuch as oxycodone, hydrocodone, or salts thereof. In another aspect, thecomposition further comprises: (d) about 0.05% to about 0.4% by mass ofBHA; and (e) about 0.05% to about 0.2% by mass of BHT. In anotheraspect, the composition comprises: (a) about 55% to about 65% by mass ofglyceryl monolinoleate; (b) about 30% to about 35% by mass ofpolyethylene oxide; and (c) about 1% to about 15% by mass of an opiodsuch as oxycodone, hydrocodone, or salts thereof. In another aspect, thecomposition further comprises: (d) about 0.1% to about 0.4% by mass ofBHA; and (e) about 0.05% to about 0.1% by mass of BHT. In anotheraspect, the composition comprises: (a) about 50% to about 70% by mass ofglyceryl monolinoleate; (b) about 25% to about 40% by mass ofpolyethylene oxide; (c) about 0.1% to about 0.4% by mass of BHA; (d)about 0.05% to about 0.1% by mass of BHT; and (e) about 1% to about 20%of by mass of an opiod such as oxycodone, hydrocodone, or salts thereof.

A common method for extracting abuse prone drugs is by boiling thecomposition. Thus, in some embodiments, the abuse deterrent matricesdescribed herein reduce the percentage of released active pharmaceuticalingredient released during boiling conditions.

In another embodiment, the abuse-deterrent composition comprises one ormore antioxidants. Suitable antioxidants comprise tocopherols (e.g.,alpha-tocopherol, beta-tocopherol, gamma-tocopherol, ordelta-tocopherol), butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), citric acid, ascorbic acid, phenolic diterpenes(e.g., carnosic acid, carnosol, rosmanol, epirosmanol, isorosmanol, ormethyl carnosate), rosmarinic acid, eugenol, eugenyl acetate, clove budextract, methanolic extract, tea catechins (e.g., epigallocatechingallate, epicatechin gallate, epigallocatechin, or epicatechin), orcombinations thereof.

In another embodiment, the abuse deterrent composition can include ahydrophilic internal phase and a lipid or lipophilic external phase(water in oil) or a lipid or lipophilic internal phase and a hydrophilicexternal phase (oil in water). The internal phase can also bestructured. A “structured” phase, as used herein, means a solid,semisolid, or a gel whose shape is relatively stable and does notusually aggregate to form a large globule. One or more structured phasesprovide controlled drug release and stabilize the physical state of thematrix. Without being bound to any theory, it is believed that astructured matrix impedes solvation and/or diffusion of the activepharmaceutical ingredient out of the matrix after the capsule shelldissolves.

In another embodiment, the active pharmaceutical ingredient can bedispersed in the internal phase as a suspension form. A suspension asused herein means the API does not dissolve in one of the phases andremains as a solid. In one embodiment, the active pharmaceuticalingredient is dispersed or suspended in the internal phase as a solidform.

In one embodiment, the pharmaceutical composition may comprise an activepharmaceutical ingredient in complex with an ion-exchange resin.Suitable ion exchange resins described herein are water-insoluble andcomprise a pharmacologically inert organic and/or inorganic matrixcontaining covalently bound functional groups that are ionic or capableof being ionized under appropriate pH conditions. The organiccomposition may be synthetic (e.g., polymers or copolymers of acrylicacid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene),or partially synthetic (e.g., modified cellulose and dextrans). Theinorganic composition preferably comprises silica gel modified by theaddition of ionic groups. Covalently bound ionic groups may be stronglyacidic (e.g., sulfonic acid, phosphoric acid), weakly acidic (e.g.,carboxylic acid), strongly basic (e.g., primary amine), weakly basic(e.g. quaternary ammonium), or a combination of acidic and basic groups.In one aspect, the ion exchange resin is a sulfonated styrene anddivinylbenzene copolymer such as polystyrene sulfonate or a salt thereof(e.g., Amberlite IRP-69).

Exemplary ion-exchangers suitable for use in ion-exchange chromatographyand for such applications as deionization of water are suitable for usein the compositions described herein. Suitable ion exchange resins arealso sold under the trade names Amberlite™ and Dowex™. Both regularlyand irregularly shaped particles may be used as resins. Regularly shapedparticles are those particles that substantially conform to geometricshapes, such as spherical, elliptical, cylindrical and the like.Irregularly shaped ion-exchange resins of this type are exemplified byAmberlite™ IRP-69, which consists of irregularly-shaped particles with asize range of 47 microns to 149 microns. Such ion-exchangers aredescribed by H. F. Walton in “Principles of Ion Exchange” (pp. 312-343)and “Techniques and Applications of Ion-Exchange Chromatography” (pp.344-361) in Chromatography. (E. Heftmann, editor), Van Nostrand ReinholdCompany, New York (1975) and in U.S. Patent Application Publication No2014/0127300, each of which is incorporated herein by reference for itsteachings of ion exchange resins thereof. Further non-limitingion-exchangers are shown in Table 3.

TABLE 3 Exemplary Cation and Anion Exchange Resins Polymer Exchangertype Amberlite IRP 69 Strong Cation Amberlite 200/200C Strong CationDOWEX ™ 50WX8H Strong Cation DOWEX ™ 88 Strong Cation Purolite ® C100HMRStrong Cation Purolite ® C100NaMR Strong Cation Purolite ® C100CaMRStrong Cation Lewatit K ® 1481 Strong Cation Lewasorb ® SW 12 StrongCation Amberlite ™ IRP 64 Weak Cation Amberlite ™ IRP 88 Weak CationPurolite ® C 115 K MR Weak Cation Purolite ® C 115 H MR Weak CationPurolite ® C 108DR Weak Cation Lewatit ® CNP 105 Weak Cation PolyAMPsOther Polyvinylsulfonic acid Other (+derivatives) Polyvinylphosphonicacid Other (+derivatives) Poly acrylic acid (+derivatives) Other

Binding of the active pharmaceutical ingredients to the resins describedherein may be accomplished using methods known in the art. For example,the general reactions may be used for a basic drug these are: (a) resin(e.g., Na⁺-form) and an ionic salt form of the drug being bound; (b)resin (e.g., Na⁻-form) plus free base form of drug.

Analogous binding reactions can be carried out for binding an acidicdrug an anion exchange resin. These are: (a) resin (e.g., Cl⁻ form) plusthe salt form of acidic drug to be bound; (b) resin (e.g., Cl⁻ form)plus the free acid form of the drug to be bound; (c) resin (e.g.,OH⁻-form) plus salt form of drug to be bound; and (d) resin (e.g.,OH⁻-form) plus free acid form of drug to be bound.

This binding may be performed, for example, as a batch or columnprocess, as is known in the art. The drug-resin complexes describedherein may be prepared by a batch process that is based on reaction theexemplary reactions described herein. The drug to be loaded on the ionexchange resin may be dissolved in an aqueous medium or in a solventmiscible with water to make a solution. The drug-containing solution isthen placed in a slurry of the resin or a column loaded with resin. Thedrug-resin resinate complex thus formed is collected by filtration andwashed with deionized or purified water to ensure removal of any unbounddrug.

In one embodiment described herein, the amount of drug loaded onto theresin to form a resinate ranges from about 1% to about 80%, includingeach integer within the specified range. In one aspect, the amount ofdrug loaded onto the resin ranges from about 10% to about 60%, includingeach integer within the specified range. In another aspect, the amountof drug loaded onto the resin ranges from about 30% to about 50%,including each integer within the specified range. In another aspect,the amount of drug loaded onto the resin comprises about 50%. In anotheraspect, the amount of drug loaded onto the resin comprises about 33%. Inanother aspect, the amount of drug loaded onto the resin comprises about25%. In another aspect, the amount of drug loaded onto the resincomprises about 20%. In another aspect, the amount of drug loaded ontothe resin comprises about 17%. In another aspect, the amount of drugloaded onto the resin comprises about 14%. In another aspect, the amountof drug loaded onto the resin comprises about 12.5%. In another aspect,the amount of drug loaded onto the resin comprises about 10%.

Another embodiment described herein is oral immediate releasepharmaceutical composition comprising one or more active pharmaceuticalingredients, one or more sequestering agents, and optionally, one ormore pharmaceutically acceptable excipients, wherein the activepharmaceutical ingredients is not pre-bound to the sequestering agent inthe dosage form. In one aspect, the quantity of active pharmaceuticalingredients (API) bound to the sequestering agent in the compositionprior to ingestion and solvation is about 0.001% to about 1% includingeach integer within the specified range. In one aspect the amount of APIpre-bound to the sequestering agent prior to ingestion is less thanabout: 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about0.5%, or about 1%. In one aspect the amount of API bound to thesequestering agent in the composition prior to ingestion is less thanabout 1%. In one aspect, the pharmaceutical composition is a dry powderadmixture of one or more sequestering agents and one or more APIs andoptionally one or more pharmaceutically acceptable excipients. Inanother aspect, the composition is a tablet, compressed tablet, orcapsule. In these compositions effectively none of the API is boud tothe sequestering agent. Dry powers of the API and sequestering agent andany excipients are merely combined, homogenized, and the dosage formproduced. The particles of the sequestering agent are incapable ofeffectively interacting with the molecules of API in the solid state ofthe composition (as compared to a solution-state binding interaction).Upon ingestion of the composition by a subject, both the sequesteringagent and API rapidly dissolve in the gastric fluid and ingestedliquid(s) in the stomach. The sequestering agent is then capable ofadsorbing a quantity of the API in situ (in the stomach) and impedes ordelays absorption of the bound API into systemic circulation.

In one embodiment, the quantity of the API adsorbed by the sequesteringagent after ingestion of a single dose of the composition is about 0.5%to about 15%, including each integer within the specified range. In oneaspect, the quantity of the API adsorbed by the sequestering agent afteringestion of a single dose of the composition is about 0.5%, about 1%,about 2.5%, about 5%, about 7.5%, about 10%, about 12%, about 15%, about20%, about 25%, or about 30%. In aspect, the quantity of the APIadsorbed by the sequestering agent after ingestion of a single dose ofthe composition is about 0.5% to about 15%.

In another embodiment, when a plurality of doses of the composition aresimultaneously ingested or successively ingested over about a 4-hourperiod, the greater quantities of sequestering agent adsorb greaterquantities of the API in situ and impede or delay absorption of thebound API into systemic circulation. Typical gastric emptying for ahuman is about 4 hours. As additional doses of the composition areingested and solvated in the stomach, greater quantities of sequesteringagent are available to adsorb the API. The principles of mass action andequilibrium binding dictate the adsorption and subsequent release of theAPI from the sequestering agent. The quantity of the API adsorbed by thesequestering agent when one or more doses of the composition is about0.5% to about 80%, including each integer within the specified range. Inone aspect the quantity of the API adsorbed by the sequestering agent isabout 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, or about 80%. In one aspect,the quantity of the API adsorbed by the sequestering agent is about 15%to about 70%.

In one embodiment, the sequestering agent is capable of adsorbing APIwhen a single dose of the composition is administered and the extentbound depends on the molar ratio of the sequestering agent's bindingsites to API. In another aspect, when a plurality of doses of thecomposition is ingested simultaneously, nearly simultaneously, or insuccession over a period of time prior to the onset of gastric emptying(ca. 4 hours), the greater quantities of sequestering agent present inthe stomach are capable of binding greater quantities of the API andconsequently delay or retard absorption of the API into the systemiccirculation. A plurality of doses can comprise 2 or more dosage forms.In one aspect, a plurality of doses comprises 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or greater than 20 doses.Without being bound by any theory, the composition described hereinreduces the C_(max) observed by delaying, retarding, or impeding theabsorption of the API into systemic circulation and can also delayT_(max). The AUC observed is proportional to the total dose of API, butthe absorption time is extended because the API is more slowly absorbedinto systemic circulation as the equilibrium shifts from sequesteringagent-bound API to free API that can be absorbed. Clearance time is alsoextended because the absorption rate constant and elimination rateconstant are both reduced. The composition mitigates accidental orintentional overingestion by precluding a bolus concentration of APIavailable for absorption that can lead to toxic C_(max) levels andconsequent physiological effects such as depressed respiration, coma,cardiac arrest, or death.

Another embodiment described herein is a composition or a method forreducing the C_(max) of an API. In one aspect the composition comprisesan oral immediate release pharmaceutical composition comprising one ormore active pharmaceutical ingredients, one or more sequestering agents,and optionally, one or more pharmaceutically acceptable excipients,wherein the active pharmaceutical ingredient is not bound to thesequestering agent in the dosage form. Another aspect is a method formaintaining a specific C_(max) of an API within a therapeuticconcentration window or below a maximum concentration comprisingadministering to a subject one or more oral immediate releasepharmaceutical compositions comprising one or more active pharmaceuticalingredients (API), optionally, one or more sequestering agents, andoptionally, one or more pharmaceutically acceptable excipients, whereless than about 1% of the API is bound to the sequestering agent, andfollowing ingestion of at least one dose by a subject, the sequesteringagent adsorbs a quantity of the API and impedes its release into thesubject's systemic circulation. In one aspect, the C_(max) of an API ina composition comprising a sequestering agent is about 10% to about 50%less than an equivalent dose of the API in a composition lacking asequestering agent including each integer within the specifiedpercentage range. In one aspect, the API's C_(max) is about 30% less;about 25% less, or about 50% less when a composition comprising asequestering agent is administered than an equivalent dose of the API ina composition lacking a sequestering agent.

Another embodiment described herein is a composition or a method formaintaining a specific concentration of an API within a therapeuticconcentration window. In one aspect the composition comprises an oralimmediate release pharmaceutical composition comprising one or moreactive pharmaceutical ingredients, one or more sequestering agents, andoptionally, one or more pharmaceutically acceptable excipients, whereinthe active pharmaceutical ingredient is not bound to the sequesteringagent in the dosage form. Another aspect is a method for maintaining aspecific concentration of an API within a therapeutic concentrationwindow comprising administering to a subject one or more oral immediaterelease pharmaceutical compositions comprising one or more activepharmaceutical ingredients (API), optionally, one or more sequesteringagents, and optionally, one or more pharmaceutically acceptableexcipients, where less than about 1% of the API is bound to thesequestering agent, and following ingestion of at least one dose by asubject, the sequestering agent adsorbs a quantity of the API andimpedes its release into the subject's systemic circulation. In anotheraspect, the method comprises acquiring a bodily fluid from the subject;measuring the concentration of the API in the subject's circulation; andaccording to the measured API concentration and a desired optimal APItherapeutic concentration, either administering one or more doses of thecomposition comprising the API and a sequestering agent; administeringan equivalent dose of the API comprising a composition lacking asequestering agent; or administering either one or more doses of thecomposition comprising the API and a sequestering agent or administeringan equivalent dose of the API comprising a composition lacking asequestering agent after a period of about 30 min to about 12 hours,including all integers within the specified time range. In one aspect,doses of the API with a sequestering agent can be titrated againstequivalent does of the same API without a sequestering agent to achievethe optimum API therapeutic plasma concentration window.

In another embodiment described herein, the drug and a sequesteringagent, such as a resin, are combined with each other in the dry state (adry admixture) so that the drug is not bound to the resin. Uponingestion, the resin and drug are solvated and the solvated resin iscapable of binding a portion of the solvated drug. In one embodiment,the quantity (mass) of resin is a multiple of the quantity (mass) ofdrug comprising a range from 1:1 to 20:1, including all ratios withinthe specified range. In some embodiments the quantity (mass) of resin isa multiple of the quantity (mass) of drug, such as: 2:1, 3:1, 4:1, 5:1,6:1, 7:1, 8:1, 9:1, or 10:1. In another embodiment, the quantity (mass)of resin is equal to the quantity (mass) of drug (1:1). An equalquantity of resin and drug by mass does not necessarily saturate theresin because the polymeric resin has many binding sites per polymer.The moles of binding sites or milliequivalents per gram of sequesteringagent can be determined by the capacity of the resin.

In another embodiment described herein, the abuse deterrent compositionsdescribed herein can prevent extraction of an active pharmaceuticalingredient through the additional means of crushing, grating, grinding,or cutting dosage forms comprising the pharmaceutical compositionsdescribed herein. In another embodiment described herein, the abusedeterrent composition also prevents the overingestion of one or moreactive pharmaceutical ingredients described herein.

In one embodiment, the composition comprises any one of the compositionsof Tables 13-17 or 19.

In another embodiment, the one or more active pharmaceutical ingredientcomprises from about 1% to about 50% of the total composition mass,including all integers within the specified range. In anotherembodiment, the one or more active pharmaceutical ingredient comprisesfrom about 1% to about 25% of the total composition mass, including allintegers within the specified range. In one aspect, the activepharmaceutical ingredient comprises about 5% of the total compositionmass. In one aspect, the active pharmaceutical ingredient comprisesabout 7% of the total composition mass. In one aspect, the activepharmaceutical ingredient comprises about 10.5% of the total compositionmass. In one aspect, the active pharmaceutical ingredient comprisesabout 20% of the total composition mass. In one aspect, the activepharmaceutical ingredient comprises about 25% of the total compositionmass.

In another embodiment, the ratio of active pharmaceutical ingredient tothe total composition ranges from about 1:100 to about 1:2, includingall iterations of ratios within the specified range. In anotherembodiment, the ratio of active pharmaceutical ingredient to the totalcomposition ranges from about 1:15 to about 1:2, including alliterations of ratios within the specified range. In one aspect, theratio of active pharmaceutical ingredient to the total composition isabout 1:100. In another aspect, the ratio of active pharmaceuticalingredient to the total composition is about 1:10. In another aspect,the ratio of active pharmaceutical ingredient to the total compositionis about 1:7.5. In another aspect, the ratio of active pharmaceuticalingredient to the total composition is about 1:5. In another aspect, theratio of active pharmaceutical ingredient to the total composition isabout 1:3. In another aspect, the ratio of active pharmaceuticalingredient to the total composition is about 1:2.

In another embodiment, the ratio of active pharmaceutical ingredient tothe resin or resinate ranges from about 1:50 to about 10:1, includingall iterations of ratios within the specified range. In anotherembodiment, the ratio of active pharmaceutical ingredient to the resinor resinate ranges from about 1:5 to about 1:1, including all iterationsof ratios within the specified range. In one aspect, the ratio of activepharmaceutical ingredient to the resin or resinate is about 1:50. Inanother aspect, the ratio of active pharmaceutical ingredient to theresin or resinate is about 1:10. In another aspect, the ratio of activepharmaceutical ingredient to the resin or resinate is about 1:5. Inanother aspect, the ratio of active pharmaceutical ingredient to theresin or resinate is about 1:2. In another aspect, the ratio of activepharmaceutical ingredient to the resin or resinate is about 1:1. Inanother aspect, the ratio of active pharmaceutical ingredient to theresin or resinate is about 2:1. In another aspect, the ratio of activepharmaceutical ingredient to the resin or resinate is about 3:1. Inanother aspect, the ratio of active pharmaceutical ingredient to theresin or resinate is about 4:1.

In one embodiment, the composition contains an active pharmaceuticalingredient in a suspended, form, soluble form, insoluble form, orcombinations thereof. In another embodiment, the composition contains anactive pharmaceutical ingredient useful for the treatment of pain. Inone embodiment, the active pharmaceutical ingredient includestapentadol, oxycodone, morphine, morphine analogues, or morphineantagonists, codeine, morphine, methadone, fentanyl and analogs, opioidpain relievers: oxycodone hydrochloride, hydrocodone bitartratehydromorphone, oxymorphone, meperidine, propoxyphene, flunitrazepam,barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines,zolpidem, zaleplon, eszopiclone, amphetamines, or methylphenidate.

In one embodiment, the composition comprises one or more activepharmaceutical ingredients (API). In one aspect, the activepharmaceutical ingredient is useful in treating pain. In one aspect, theactive pharmaceutical ingredient is tapentadol, oxycodone, hydrocodone,or codeine. In one aspect, the active pharmaceutical ingredient isoxycodone or hydrocodone.

Examples of specific active drug substances suitable for use in thepharmaceutical compositions provided herein include: anti-inflammatoryand antirheumatic active drug substances, such as, for example:butylpyrazolidine, phenylbutazone, mofebutazone, oxyphenbutazone,clofezone, kebuzone, acetic acid derivatives and related substances,indometacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac,bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide,oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, oxicam,piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate,propionic acid derivatives, ibuprofen, naproxen, ketoprofen, fenoprofen,fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen,tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen,alminoprofen, dexketoprofen, fenamates, mefenamic acid, tolfenamic acid,flufenamic acid, meclofenamic acid, coxibs, celecoxib, rofecoxib,valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumicacid, azapropazone, glucosamine, benzydamine, glucosaminoglycanpolysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein,morniflumate, tenidap, oxaceprol, chondroitin sulfate, feprazone,dipyrocetyl, acetylsalicylic acid, quinolines, oxycinchophen, goldpreparations, sodium aurothiomalate, sodium aurotiosulfate, auranofin,aurothioglucose, aurotioprol, penicillamine or bucillamine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise analgesics, such as, for example: opioids, natural opiumalkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone,dihydrocodone, diamorphine, tapentadol, papaveretum, papaveretum,codeine, phenylpiperidine derivatives, ketobemidone, pethidine,fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide,dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives,pentazocine, phenazocine, oripavine derivatives, buprenorphine,morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol,dezocine, salicylic acid and derivatives, acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, pyrazolones, phenazone, metamizole sodium,aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,phenacetin, bucetin, propacetamol, other analgesics and antipyretics,such as, for example: rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, or ziconotide.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anaesthetics, such as, for example: ethers, diethyl ether,vinyl ether, halogenated hydrocarbons, halothane, chloroform,methoxyflurane, enflurane, trichloroethylene, isoflurane, desflurane,sevoflurane, barbiturates, methohexital, hexobarbital, thiopental,narcobarbital, opioid anaesthetics, fentanyl, alfentanil, sufentanil,phenoperidine, anileridine, remifentanil, other general anaesthetics,such as, for example: droperidol, ketamine, propanidid, alfaxalone,etomidate, propofol, hydroxybutyric acid, nitrous oxide, esketamine,xenon, esters of aminobenzoic acid, metabutethamine, procaine,tetracaine, chloroprocaine, benzocaine, amides, bupivacaine, lidocaine,mepivacaine, prilocaine, butanilicaine, cinchocaine, etidocaine,articaine, ropivacaine, levobupivacaine, esters of benzoic acid,cocaine, other local anaesthetics, such as, for example: ethyl chloride,dyclonine, phenol, or capsaicin.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antimigraine active drug substances, such as, for example:ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride,corticosteroid derivatives, flumedroxone, selective serotonin (5HT¹)agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan,almotriptan, eletriptan, frovatriptan, other antimigraine preparations,pizotifen, clonidine, iprazochrome, dimetotiazine, or oxetorone.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antiepileptic active drug substances, such as, for example:barbiturates and derivatives, methylphenobarbital, phenobarbital,primidone, barbexaclone, metharbital, hydantoin derivatives, ethotoin,phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin,fosphenytoin, oxazolidine derivatives, paramethadione, trimethadione,ethadione, succinimide derivatives, ethosuximide, phensuximide,mesuximide, benzodiazepine derivatives, clonazepam, carboxamidederivatives, carbamazepine, oxcarbazepine, rufinamide, fatty acidderivatives, valproic acid, valpromide, aminobutyric acid, vigabatrin,progabide, tiagabine, other antiepileptics, such as, for example:sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin,pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol,lacosamide, or beclamide.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anticholinergic active drug substances, such as, for example:tertiary amines, trihexyphenidyl, biperiden, metixene, procyclidine,profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine,tropatepine, ethers chemically close to antihistamines, etanautine,orphenadrine (chloride), ethers of tropine or tropine derivatives,benzatropine, or etybenzatropine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise dopaminergic active drug substances, such as, for example: dopaand dopa derivatives, levodopa, melevodopa, etilevodopa, adamantanederivatives, amantadine, dopamine agonists, bromocriptine, pergolide,dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline,apomorphine, piribedil, rotigotine, monoamine, oxidase B inhibitors,selegiline, rasagiline, other dopaminergic agents, such as, for example:tolcapone, entacapone, or budipine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antipsychotic active drug substances, such as, for example:phenothiazines with aliphatic side-chain, chlorpromazine,levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine,chlorproethazine, phenothiazines with piperazine structure, dixyrazine,fluphenazine, perphenazine, prochlorperazine, thiopropazate,trifluoperazine, acetophenazine, thioproperazine, butaperazine,perazine, phenothiazines with piperidine structure, periciazine,thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives,haloperidol, trifluperidol, melperone, moperone, pipamperone,bromperidol, benperidol, droperidol, fluanisone, indole derivatives,oxypertine, molindone, sertindole, ziprasidone, thioxanthenederivatives, flupentixol, clopenthixol, chlorprothixene, tiotixene,zuclopenthixol, diphenylbutylpiperidine derivatives, fluspirilene,pimozide, penfluridol, diazepines, oxazepines, thiazepines, loxapine,clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine,benzamides, sulpiride, sultopride, tiapride, remoxipride, amisulpride,veralipride, levosulpiride, lithium, other antipsychotics, such as, forexample prothipendyl, risperidone, clotiapine, mosapramine, zotepine,aripiprazole, or paliperidone.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anxiolytic active drug substances, such as, for example:benzodiazepine derivatives, diazepam, chlordiazepoxide, medazepam,oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam,clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam,camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam,clotiazepam, cloxazolam, tofisopam, diphenylmethane derivatives,hydroxyzine, captodiame, carbamates, meprobamate, emylcamate,mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine,azaspirodecanedione derivatives, buspirone, other anxiolytics, such as,for example: mephenoxalone, gedocarnil, or etifoxine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise hypnotic and sedative active drug substances, such as, forexample: barbiturates, pentobarbital, amobarbital, butobarbital,barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital,cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital,thiopental, ethallobarbital, allobarbital, proxibarbal, aldehydes andderivatives, chloral hydrate, chloralodol, acetylglycinamide chloralhydrate, dichloralphenazone, paraldehyde, benzodiazepine emeproniumderivatives, flurazepam, nitrazepam, flunitrazepam, estazolam,triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam,loprazolam, doxefazepam, cinolazepam, piperidinedione derivatives,glutethimide, methyprylon, pyrithyldione, benzodiazepine related drugs,zopiclone, zolpidem, zaleplon, ramelteon, other hypnotics and sedatives,such as, for example: methaqualone, clomethiazole, bromisoval,carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol,valerian, hexapropymate, bromides, apronal, valnoctamide,methylpentynol, niaprazine, melatonin, dexmedetomidine, ordipiperonylaminoethanol.

In another embodiment, suitable active pharmaceutical ingredients cancomprise antidepressant active drug substances, such as, for example:non-selective monoamine reuptake inhibitors, desipramine, imipramine,imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine,dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin,iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine,amineptine, maprotiline, quinupramine, selective serotonin reuptakeinhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline,alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidaseinhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine,iproniazide, iproclozide, monoamine oxidase A inhibitors, moclobemide,toloxatone, other antidepressants, such as, for example: oxitriptan,tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine,bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine,tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone,duloxetine, agomelatine, desvenlafaxine, centrally actingsympathomimetics, such as, for example: amfetamine, dexamfetamine,lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate,pemoline, fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline,xanthine derivatives, caffeine, propentofylline, other psychostimulantsand nootropics, such as, for example meclofenoxate, pyritinol,piracetam, deanol, fipexide, citicoline, oxiracetam, pirisudanol,linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone,prolintane, pipradrol, pramiracetam, adrafinil, or vinpocetine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise anti-dementia active drug substances, such as, for example:anticholinesterases, tacrine, donepezil, rivastigmine, galantamine,other anti-dementia drugs, memantine, or ginkgo biloba.

In another embodiment, suitable active pharmaceutical ingredients cancomprise other nervous system active drug substances, such as, forexample: parasympathomimetics, anticholinesterases, neostigmine,pyridostigmine, distigmine, ambenonium, choline esters, carbachol,bethanechol, and other parasympathomimetics, such as, for example,pilocarpine, or choline alfoscerate.

Active drug substances used in addictive disorders, such as, forexample: nicotine, bupropion, varenicline, disulfiram, calciumcarbimide, acamprosate, naltrexone, buprenorphine, methadone,levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine,acetylleucine, gangliosides and ganglioside derivatives, tirilazad,riluzole, xaliproden, hydroxybutyric acid, or amifampridine.

In another embodiment, suitable active pharmaceutical ingredients cancomprise opium alkaloids and derivatives, such as, for example:ethylmorphine, hydrocodone, codeine, opium alkaloids with morphine,normethadone, noscapine, pholcodine, dextromethorphan, thebacon,dimemorfan, acetyldihydrocodone, benzonatate, benproperine, clobutinol,isoaminile, pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate,bibenzonium bromide, butamirate, fedrilate, zipeprol, dibunate,droxypropine, prenoxdiazine, dropropizine, cloperastine, meprotixol,piperidione, tipepidine, morclofone, nepinalone, levodropropizine, ordimethoxanate.

In another embodiment, the active pharmaceutical ingredient may be asubstance with abuse potential that presents a safety risk. Such activedrug substance may include: 1-(1-phenylcyclohexyl)pyrrolidine,1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine,1-[1-(2-thienyl)-cyclohexylpiperidine,1-[1-(2-thienyl)cyclohexyl]pyrrolidine,1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, 2,5-dimethoxy-4-ethylamphetamine,2,5-dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine),2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I(4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2(2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4(2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7(2,5-dimethoxy-4-(n)-propylthiophenethylamine),3,4-methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine,3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine,3-methylfentanyl, 3-methylthiofentanyl,4-brorno-2,5-dimethoxyamphetamine, 4-bromo-2,5-dimethoxyphenethylamine,4-methoxyamphetamine, 4-methyl-2,5-dimethoxyamphetamine,4-methylaminorex (cis isomer), 5-MeO-DIPT(5-methoxy-N,N-diisopropyltryptamine), 5-MeO-DMT(5-methoxy-N,N-dimethyltryptamine),5-methoxy-3,4-methylenedioxyamphetamine, acetorphine, acetorphine,acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl,acetyldihydrocodone, acetylmethadol, acetylmethadol, alfentanil,allobarbital, allylprodine, alphacetylmethadol exceptlevo-alphacetylmethadol, alpha-ethyltryptamine, alphameprodine,alphamethadol, alphamethadol, alpha-methylfentanyl,alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon,amfetaminil, amineptin, aminorex, amobarbital, amphetamine,dextroamphetamine, amilnitrite (all isomers of the amyl group), anabolicsteroids, anileridine, aprobarbital, barbital, barbituric acidderivative, BDB (3,4-methylenedioxyphenyl)-2-butanamine), benzethidin,benzethidine, benzoylecgonine, benzphetamine, benzphetamine,benzylmethylcetone, benzylmorphine, betacetylmethadol,beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, betameprodine,betameprodine, betamethadol, betaprodine, bezitramide, bezitramide,boldenone, brolamfetamine, bromazepam, brotizolam, bufotenine,buprenorphine, butabarbital, butalbital, butobarbital, butorphanol, BZP(A2)(1-benzylpiperazin), camazepam, cannabis, carfentanil, catha edulis,cathine, cathinone, chloral betaine, chloral hydrate, chlordiazepoxide,chlorhexadol, chlorotestosterone (same as clostebol), chlorphentermine,clobazam, clonazepam, clonitazene, clonitazene, clorazepate,clortermine, clostebol, clotiazepam, cloxazolam, coca leaves, cocaine,codeine, codeine and isoquinoline alkaloid, codeine methylbromide,codeine-N-oxide, codoxime, cyclobarbital (hexemal NFN), cyprenorphine,dehydrochlormethyltestosterone, delorazepam, desomorphine,dexamfetamine, dexfenfluramine, dexmethylphenidate, dextromoramide,dextropropoxyphene, diacetylmorphine, diampromide, diazepam,dichloralphenazone, diethylpropion, diethylthiambutene,diethyltryptamine, difenoxin, dihydrocodone, dihydroetorphine,dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol,dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate,diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone,drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethylloflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine,ethylmorphine, eticyclidine, etilamfetamine, etonitazene, etorphine,etoxeridine, etryptamine, fencamfamin, fenethylline, fenetylline,fenfluramine, fenproporex, fentanyl, fludiazepam, flunitrazepam,fluoxymesterone, flurazepam, formebolone, fungi and spores of thespecies psilocybe semilanceata, furethidine, gamma hydroxybutyric acid,glutethimide, halazepam, haloxazolam, heroine, hydrocodone, hydrocodone& isoquinoline alkaloid, hydromorphinol, hydromorphone,hydroxypethidine, ibogaine, isobutyl nitrite, isomethadone, ketamine,ketazolam, ketobemidone, levamfetamine, levo-alphacetylmethadol,levo-methamphetamine, levomethorphan, levomoramide, levophenacylmorphan,levorphanol, lisdexamfetamine, loprazolam, lorazepam, lormetazepam,lysergic acid, lysergic acid amide, lysergic acid diethylamide,marijuana, mazindol, MBDN(N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP(1-(3-chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam,mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine, meperidineintermediate, meprobamate, mescaline, mesocarb, mesterolone,metamfetamine, metazocine, methadone, methadone intermediate,methamphetamine, methandienone, methandrolone, methandriol,methandrostenolone, methaqualone, methcathinone, methenolone,methohexital, methyldesorphine, methyldihydromorphine, methylphenidate,methylphenobarbital (mephobarbital), methyltestosterone, methyprylone,metopone, mibolerone, midazolam, modafinil, moramide-intermediate,morpheridine, morphine, morphine methylbromide, morphinemethylsulfonate, morphine-N-oxide, myrophine, N,N-dimethylamphetamine,nabilone, nalorphine, nandrolone, N-ethyl-1-phenylcyclohexylamine,N-ethyl-3-piperidyl benzilate, N-ethylamphetamine,N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine,nicodicodine, nicomorphine, nimetazepam, nitrazepam,N-methyl-3-piperidyl benzilate, noracymethadol, norcodeine, nordiazepam,norethandrolone, norlevorphanol, normethadone, normorphine, norpipanone,norpipanone, opium, oxandrolone, oxazepam, oxazolam, oxycodone,oxymesterone, oxymetholone, oxymorphone, para-fluorofentanyl, parahexyl,paraldehyde, pemoline, pentazocine, pentobarbital, petrichloral, peyote,phenadoxone, phenampromide, phenazocine, phencyclidine, phendimetrazine,phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine,phenylacetone, pholcodine, piminodine, pinazepam, pipradrole,piritramide, PMMA (paramethyxymethyl amphetamine), prazepam,proheptazine, properidine, propiram, psilocybine, psilocine,pyrovalerone, quazepam, racemethorphane, racemoramide, racemorphane,remifentanil, salvia divinorum, salvinorin A, secobarbital,secobarbital, sibutramine, SPA, stanolone, stanozolol, sufentanil,sulfondiethylmethane, sulfonethylmethane, sulfonmethane, talbutal,temazepam, tenamfetamine, testolactone, testosterone,tetrahydrocannabinols, tetrazepam, TFMPP(1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine, thiamylal,thiofentanyl, thiopental, tiletamine and zolazepam in combination,tilidine, trenbolone, triazolam, trimeperidine, vinbarbital, zaleplon,zipeprol, zolpidem, or zopiclone.

Other suitable examples of active drug substances suitable for use inthe pharmaceutical compositions described herein include, for example,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodone, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, dextropropoxyphene, ketobemidone, levallorphan,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, morphine 6-glucuronide,morphine 3-glucuronide, myrophine, nalbuphine, narcine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxycodeine, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, thebaine,levo-alphacetylmethadol (LAAM), remifentanil, carfentanyl, ohmefentanyl,MPPP, prodine, PEPAP, levomethorphan, etorphine, lefetamine, loperamide,diphenoxylate, or pethidine.

Other examples of active drug substances suitable for use in thepharmaceutical compositions described herein include anabolic steroids,cannabis, cocaine, or diazepam.

In another embodiment, the active drug substance comprises thetherapeutic classes including non-steroidal anti-inflammatory substancesor antirheumatic active drug substances.

In other embodiments, the active drug substance comprises analgesics,opioids, antipyretics, anaesthetics, antimigraine agents,antiepileptics, anti-parkinson agents, dopaminergic agents,antipsychotics, anxiolytics, sedatives, antidepressants,psychostimulants agents, dopamine, noradrenaline, nicotinic,alfa-adrenergic, serotonin, H3 antagonists used for ADHD or nootropicsagents used in addictive disorders.

In other embodiments, the active drug substance comprises therapeuticclasses including anaesthetics, centrally acting analgesics,sedative-hypnotics, anxiolytics, appetite suppressants, decongestants,antitussives, antihistamines, antiemetics, antidiarrheals, and drugsused to treat narcolepsy, or attention deficit hyperactivity disorder.

In another embodiment, the active drug substance is associated withabuse syndromes and the active drug substance may, for example, beselected from opioids, CNS depressants, CNS stimulants, cannabinoids,nicotine-like compounds, glutamate antagonists, or N-methyl-D-aspartate(NMDA) antagonists.

In another embodiment, the active drug substance is an analgesic.Examples of analgesics suitable for use in the pharmaceuticalcompositions described herein include, for example, opioids, naturalopium alkaloids, morphine, opium, hydromorphone, nicomorphine,oxycodone, dihydrocodone, diamorphine, tapentadol, papaveretum, codeine,phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl,diphenylpropylamine derivatives, dextromoramide, piritramide,dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives,pentazocine, phenazocine, oripavine derivatives, buprenorphine,morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol,dezocine, salicylic acid and derivatives, acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, pyrazolones, phenazone, metamizole sodium,aminophenazone, propyphenazone, nifenazone, anilides, paracetamol,phenacetin, bucetin, propacetamol, other analgesics and antipyreticssuch as, for example, rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, or ziconotide.

In another embodiment, the active drug substance is an opioid. Where anopioid is included as an active drug substance, the opioid may comprisenaturally occurring opioids, synthetic opioids, or semisyntheticopioids.

In other embodiment, the active drug substance comprises amfetamine,dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate,dexmethylphenidate, or combinations thereof.

In another embodiment, the pharmaceutical compositions disclosed hereinincludes an opioid, the opioid is selected from buprenorphine, codeine,dextromoramide, dihydrocodone, fentanyl, hydrocodone, hydromorphone,morphine, pentazocine, oxycodeine, oxycodone, oxymorphone,norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol,tapentadol, or dihydromorphine.

Where an opioid is used as an active drug substance, the opioid may bepresent in any of its crystalline, polymorphous, semi-crystalline, andamorphous or polyamorphous forms. Furthermore, in another embodiment, anopioid used as an active drug substance may be present in one or moreforms selected from its crystalline, polymorphous, semi-crystalline, oramorphous or polyamorphous forms.

Some embodiments of the pharmaceutical compositions disclosed hereininclude an opioid as an active drug substance, the active drug substanceis selected from morphine, oxycodone, hydrocodone, hydromorphone,norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode andpharmaceutically acceptable salts thereof, including oxycodonehydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride ormorphine sulphate pentahydrate.

In other embodiments, the pharmaceutical compositions as describedherein are suitable for use for water soluble as well as slightlysoluble or insoluble active drug substances.

In another embodiment, all of the above mentioned active drug substancesmay also be in the form of pharmaceutically acceptable salts, unchargedor charged molecules, molecular complexes, solvates, or anhydratesthereof, and, if relevant, single isomers, enantiomers, racemicmixtures, or mixtures thereof.

In another embodiment, the pharmaceutical compositions described hereinmay comprise pharmaceutically acceptable salts of any of the abovementioned active drug substances.

In another embodiment, the active pharmaceutical ingredient ishydrocodone or oxycodone or a pharmaceutically acceptable salt form ofeither hydrocodone or oxycodone. Pharmaceutically acceptable salts formsare those formed by contacting hydrocodone or oxycodone free base with asuitable acid in a suitable solvent under suitable conditions that willform a form of hydrocodone or oxycodone acid addition salt. Suitableacids include hydrochloric acid, camphorsulfonic acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, tartaric acid, mandelic acid, malic acid, salicylicacid, fumaric acid, lactic acid, citric acid, glutamic acid, and/oraspartic acid.

The term “pharmaceutically acceptable salts” of an active drug substanceincludes alkali metal salts such as, for example, sodium or potassiumsalts, alkaline earth metal salts such as, for example, calcium andmagnesium salts, and salts with organic or inorganic acid such as, forexample, hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, citric acid, formic acid, maleic acid, succinicacid, tartaric acid, methanesulphonic acid, toluenesulphonic acid etc.In another embodiment, pharmaceutically acceptable opioid salts cancomprise sulphate salts, hydrochloride salts, and bitartrate salts.

In another embodiment, the active pharmaceutical ingredient may be inany of its crystalline, polymorphous, semi-crystalline, amorphous orpolyamorphous forms or mixtures thereof.

The concentration of the active drug substance in the pharmaceuticalcomposition for use according to the disclosure depends on the specificactive drug substance, the disease to be treated, the condition of thepatient, the age, and gender of the patient, etc. The above-mentionedactive drug substances may be known active drug substances and a personskilled in the art will be able to find information as to the dosage ofeach active drug substance and, accordingly, will know how to determinethe amount of each active drug substance in the pharmaceuticalcomposition.

The active pharmaceutical ingredient may be a new chemical entity forwhich the amount of information is limited. In such cases, the dosagehas to be evaluated based on available preclinical and/or clinical data.

In one embodiment described herein, the pharmaceutical compositioncomprises soft capsule shell comprising a matrix comprising an activepharmaceutical ingredient.

In one embodiment described herein, the soft capsule shell has thecomposition of Table 4, including all possible iterations of thespecified ranges that provide 100% for the total weight percentage,including or excluding the optional colorings, flavorings, orexcipients.

TABLE 4 Exemplary soft gelatin capsule composition Weight ExemplaryPercentage Component Component (%) Film-forming polymer Gelatin   20-36(Gelatin) Plasticizer Glycerol   10-30 Solvent Water   20-70 Opacifier(optional) Titanium dioxide  0.5-1.5 Coloring agent (optional) Various0.05-0.1 TOTAL 100%

Film-former polymers that are useful for creating soft capsules aregelatin, hydroxypropylmethylcellulose (HPMC) or carrageenan (e.g., iotacarrageenan and kappa carrageenan). In one aspect of the enteric softcapsule shell described herein, the film-forming polymer is gelatin. Inanother aspect of the enteric soft capsule shell described herein, thefilm-forming polymer is carrageenan.

Plasticizers that are useful for creating soft capsules as describedherein are glycerol, sorbitol, polyethylene glycols, or combinationsthereof. The weight ratio between the film-forming polymer, plasticizer,and solvent is adjusted so that the gel mass is flowable and not tooviscous, and can be made into soft capsules using rotary dieencapsulation methods.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 5.

TABLE 5 Exemplary Soft Capsule Shell Composition Percent weightComponent (%) Gelatin 43 Glycerol 20 Titanium dioxide (optional) 0.7Coloring agent (optional) 0.1 Water 36.2 TOTAL 100% Final pH ~4-7 Ratiototal plasticizer to gelatin 20:43 (0.46:1) Water content in dried softcapsule shell: 8-15%

In one embodiment described herein, the soft capsule comprises about 43%of at least one film-forming polymer; about 20% of at least oneplasticizer; about 36% water; optionally, about 0.7% titanium dioxide;and optionally, about 0.1% of at least one coloring agent.

In one embodiment described herein, the enteric soft capsule describedherein comprises a composition of about 3% to about 10% film formingpolymer (e.g., a composition of carrageenan); about 10% to about 30%filler; about 10% to about 30% plasticizer; and about 30% to about 70%solvent.

In one embodiment, the weight percentage range of film-forming polymerof the soft capsule described herein is about 20% to about 45%,including all integers within the specified range. In one aspect, thefilm-forming polymer weight percentage is about 20%. In one aspect, thefilm-forming polymer weight percentage is about 25%. In one aspect, thefilm-forming polymer weight percentage is about 30%. In one aspect, thefilm-forming polymer weight percentage is about 35%. In one aspect, thefilm-forming polymer weight percentage is about 38%. In another aspect,the film-forming polymer weight percentage is about 42%. In anotheraspect, the film-forming polymer weight percentage is about 44%.

In one embodiment, the weight percentage range of plasticizer is about15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the plasticizer weight percentage isabout 17%. In another aspect, the plasticizer weight percentage is about18.5%. In another aspect, the plasticizer weight percentage is about20%.

In one embodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.33:1 to about 0.56:1, including alliterations of iterations of ratios with the specified range. In oneembodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.38:1. In one embodiment, the weightpercentage ratio range of plasticizer to film-forming polymer is about0.42:1. In one embodiment, the weight percentage ratio range ofplasticizer to film-forming polymer is about 0.46:1. In one embodiment,the weight percentage ratio range of plasticizer to film-forming polymeris about 0.52:1.

In one aspect, soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingsoft capsules comprising the pharmaceutical composition as describedherein. The process includes preparing a gel mass composition comprisinga film-forming, water-soluble polymer, an appropriate plasticizer, andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The thickness ofthe films or ribbons that form the soft capsule shell is from about0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm), including allintegers within the specified range. The shell thickness can be about0.010 inch (≈0.254 mm), about 0.015 inch (≈0.381 mm), about 0.02 in(≈0.508 mm), about 0.03 in (≈0.762 mm), about 0.04 in (≈1.02 mm), orabout 0.05 in (≈1.27 mm). In one embodiment, the thickness is about 0.02inches (≈0.508 mm) to about 0.040 inches (≈1.02 mm). In one embodiment,the shell thickness is about 0.028 inches (≈0.711 mm). In anotherembodiment, the shell thickness is about 0.033 inches (≈0.838 mm). Inanother embodiment, the shell thickness is about 0.038 inches (≈0.965mm).

In one embodiment described herein, the soft capsule shell describedherein, encapsulates a matrix fill as described herein. In anotherembodiment described herein, the soft capsule shell and encapsulatedmatrix fill comprises an outer dimension from about 2 oval to about 30oval including all iterations of capsule size within the specified range(e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval,12 oval, 16 oval, 20, or 30 oval). In another embodiment describedherein, the soft capsule shell and encapsulated matrix fill comprises anouter dimension from about 2 round to about 28 round including alliterations of capsule size within the specified range (e.g., 2 round, 3round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round,16 round, 20 round or 28 round). In another embodiment described herein,the soft capsule shell and encapsulated matrix fill comprises an outerdimension from about 2 oblong to about 22 oblong including alliterations of capsule size within the specified range (e.g., 2 oblong, 3oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).Dimension specifications of soft capsules and tablets are known to thoseskilled in the art. See Remington's Essentials of Pharmaceutics,Pharmaceutical Press Publishing Company, London, UK, 1^(st) Edition,2013, which is incorporated by reference herein for such teachings.

In another embodiment described herein, the pharmaceutical compositioncomprises an enteric soft capsule shell comprising a matrix fillcomprising an active pharmaceutical ingredient.

Enteric soft capsules are described in International Patent ApplicationPublication No. WO 2004/030658; U.S. Patent Application Publication No.US 2006/0165778; and U.S. Pat. No. 8,685,445, each of which isincorporated by reference herein for such teachings. The enteric softcapsule shell may comprise one or more film forming polymers, one ormore enteric acid-insoluble polymers, one or more plasticizers, one ormore alkali-neutralizing agents, one or more solvents, optionally one ormore colorants, and optionally one or more flavorings or otherconventionally accepted pharmaceutical excipients or additives.

Film-former polymers that are useful for creating enteric soft capsulesare gelatin, hydroxypropylmethylcellulose (HPMC) or carrageenan (e.g.,iota carrageenan and kappa carrageenan). In one aspect of the entericsoft capsule shell described herein, the film-forming polymer isgelatin. In another aspect of the enteric soft capsule shell describedherein, the film-forming polymer is carrageenan.

Examples of enteric, acid-insoluble polymers are acrylic andmethacrylate acid copolymers, cellulose acetate phthalate (CAP),cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate(HPMCP), algenic acid salts such as sodium or potassium alginate, orshellac. Poly(methacylic acid-co-methyl methacrylate) anionic copolymersbased on methacrylic acid and methyl methacrylate are particularlystable and are preferred in some embodiments. Poly(meth)acrylates(methacrylic acid copolymer), available under the trade name EUDRAGIT®(Evonik Industries AG, Essen, Germany), are provided as powder oraqueous dispersions. In one aspect, the methacrylic acid copolymer canbe EUDRAGIT® L 30 D-55; EUDRAGIT® L 100-55; EUDRAGIT® L 100; EUDRAGIT® L12.5; EUDRAGIT® S 100; EUDRAGIT® S 12.5; EUDRAGIT® FS 30 D; EUDRAGIT® E100; EUDRAGIT® E 12.5; EUDRAGIT® E PO; EUDRAGIT® RL 100; EUDRAGIT® RLPO; EUDRAGIT® RL 30 D; EUDRAGIT® RL 12.5; EUDRAGIT® RS 100; EUDRAGIT® RSPO; EUDRAGIT® RS 30 D; EUDRAGIT® RS 12.5; EUDRAGIT® NE 30 D; EUDRAGIT®NE 40 D; EUDRAGIT® NM 30 D; or other poly(meth)acrylate polymers. In oneaspect, the enteric polymer is EUDRAGIT® L 100, a methacrylic acidcopolymer, Type A. Acid-insoluble polymer specifications are detailed inthe United States Pharmacopoeia and in various monographs.

Plasticizers that are useful for creating enteric soft capsules asdescribed herein are glycerol, sorbitol, polyethylene glycol, citricacid, citric acid esters, such as tri-ethyl citrate, or combinationsthereof. The weight ratio between the film-forming polymer, the entericacid-insoluble polymer, and plasticizer is adjusted so that the gel massis flowable and not too viscous, and can be made into soft capsulesusing rotary die encapsulation methods.

In one embodiment, enteric soft capsule shell compositions can be madeby dissolving the enteric acid-insoluble polymer in an aqueous solutionof an alkali neutralizing agent such as ammonia, sodium hydroxide,potassium hydroxide, or liquid amines such as tri-ethanol amine orethylene diamine. The amount of alkali is adjusted to give a final pHvalue of the gel mass less than or equal to about pH 9.0. In oneembodiment, the final pH does not exceed 8.5. The volatile alkalineutralizing agent, ammonia is preferred. The film-forming polymer canthen be combined with the plasticizer and solvent and then blended withthe acid-insoluble gel to make a final homogeneous mix in aheat-controlled vessel and can be degassed by using vacuum. The fugitiveammonia evaporates during degassing. Using the foregoing process, thealkali concentrations do not require an additional step such as heatingor neutralizing with acid in order to neutralize the gel mass.

In another embodiment described herein, an enteric soft capsule shellcan be made by using an aqueous dispersion of the acid-insoluble polymerby adding alkaline materials such as ammonium, sodium, or potassiumhydroxides, other alkalis, or a combination thereof that will cause theenteric acid-insoluble polymer to dissolve. The plasticizer-wetted,film-forming polymer can then be mixed with the solution of theacid-insoluble polymer. In one embodiment, enteric acid-insolublepolymers in the form of salts of the above-mentioned bases or alkaliscan be dissolved directly in water and mixed with theplasticizer-wetted, film-forming polymer.

In one embodiment, an enteric soft capsule shell has the composition ofTable 6, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 6 Exemplary Enteric Soft Capsule Shell Composition CompositionRange Component Exemplary Component (%) Film-forming polymer Gelatin20-36 Enteric, acid insoluble polymer Methacrylic Acid Copolymer  8-20Plasticizer Glycerol, Triethyl citrate 15-22 Alkali neutralizing agentsNH₄OH (30%), NaOH 1-5 Solvent Water 20-40 Opacifier Titanium Dioxide  1-7.5 Colorant (optional) Various 0.05-1   Flavoring (optional)Various 0.05-2   Excipients (optional) Various 1-5

In one embodiment, an enteric soft capsule shell comprises a compositionof about 30% film forming polymer (e.g., gelatin); about 10% enteric,acid insoluble polymer; about 20% plasticizer; about 1% alkalineutralizing agent; and about 37% solvent.

In one embodiment described herein, the enteric soft capsule describedherein comprises a composition of about 3% film forming polymer (e.g., acomposition of carrageenan); about 10% enteric, acid insoluble polymer;about 10% filler; about 10% plasticizer; about 1% alkali neutralizingagent; about 2% sealant; and about 60% solvent.

In one embodiment, the weight percentage range of total polymer content(i.e., film forming polymer and enteric acid-insoluble polymer) of theenteric soft capsule described herein is about 30% to about 45%,including all integers within the specified range. In anotherembodiment, the weight percentage range of total polymer content (i.e.,film forming polymer and enteric acid-insoluble polymer) of the entericsoft capsule described herein is about 9% to about 35%, including allintegers within the specified range. In one aspect, the total polymerweight percentage is about 40%. In another aspect, the total polymerweight percentage is about 42%. In another aspect, the total polymerweight percentage is about 45%. In another aspect, the total polymerweight percentage is about 38%. In another aspect, the total polymerweight percentage is about 12%. In another aspect, the total polymerweight percentage is about 16%.

In one embodiment, the weight percentage range of total plasticizer isabout 15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the total plasticizer weight percentageis about 19%. In another aspect, the total plasticizer weight percentageis about 17.7%. In another aspect, the total plasticizer weightpercentage is about 18.9%. In another aspect, the total plasticizerweight percentage is about 19.3%.

In one embodiment, the alkali neutralizing-agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage ofabout 1 to about 5% of the total enteric soft capsule composition. Inone aspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2%. In another aspect, 30% w/v ammonia is added to a weightpercentage of about 1.7%. In one aspect, ammonia is added to provide afinal pH of about 9 in the enteric soft capsule composition. In anotheraspect, ammonia is added to provide a final pH of about 8.5 in theenteric soft capsule composition. In another aspect, after the capsulesare filled and dried, the ammonia concentration is substantiallyreduced, owing to the fugitive nature of the volatile alkali. In oneaspect, practically all of the ammonia is evaporated except for ammoniumions comprising salts with other moieties in the composition.

In one embodiment, the weight ratio range of film forming polymer toenteric acid insoluble polymer (film forming: enteric) is about 25:75(≈0.33) to about 40:60 (≈0.67) (i.e., ≈0.33-0.67), including alliterations of ratios within the specified range. In one aspect, theratio of film forming polymer to enteric acid insoluble polymer is about30:70 (≈0.43). In another aspect, the ratio of film forming polymer toenteric acid insoluble polymer is about 28:72 (≈0.38).

In another embodiment described herein, the weight ratio range of filmforming polymer (i.e., total carrageenan composition) to enteric acidinsoluble polymer (film forming: enteric) in the enteric soft gelcomposition is about 3:9 (≈0.3) to about 4:3 (≈1.3) (i.e., ≈0.3-1.3),including all ratios within the specified range. In some aspects, theratio of film forming polymer to enteric acid insoluble polymer in thegel mass is about 1:3 (≈0.33), about 1:2.5 (≈0.4), about 1:2 (≈0.5),about 1:1.6 (≈0.6), about 1:1.25 (≈0.8), about 1:1 (≈1), about 1.1:1(≈1.1), about 1.21 (≈1.2), or about 1.3:1 (≈1.3). In one aspect, theratio of film forming polymer to enteric acid insoluble polymer in thegel mass is about 1:2.5 (≈0.4). In another aspect, the ratio of filmforming polymer to enteric acid insoluble polymer is about 1:3 (≈0.3).

In one embodiment, the weight ratio of total plasticizer to film formingpolymer is about 20:40 to 21:30 (i.e., ≈0.5-0.7), including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to film forming polymer is about 20:40(≈0.5). In another aspect, the weight ratio of total plasticizer to filmforming polymer is about 21:30 (≈0.7). In another aspect, the weightratio of total plasticizer to film forming polymer is about 19:29(≈0.65). In another aspect, the weight ratio of total plasticizer tofilm forming polymer is about 19.3:29.2 (≈0.66).

In one embodiment, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 1:1 to about 2:1 (≈1-2), including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to enteric acid insoluble polymer isabout 11:10 (≈1.1). In another aspect, the weight ratio of totalplasticizer to enteric acid insoluble polymer is about 14:10 (≈1.4). Inanother aspect, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 17:10 (≈1.7). In another aspect, the weightratio of total plasticizer to enteric acid insoluble polymer is about20:10 (≈2). In another aspect, the weight ratio of total plasticizer toenteric acid insoluble polymer is about 19.3:11.2 (≈1.73).

In one embodiment, the weight ratio range of total plasticizer to totalpolymer (film forming and enteric acid insoluble polymer) is about 18:45to about 20:40 (i.e., ≈0.40-0.5), including all iterations of ratioswithin the specified range. In one aspect, the weight ratio range oftotal plasticizer to total polymer is about 18:45 (≈0.40). In anotheraspect, the weight ratio range of total plasticizer to total polymer isabout 19:40 (≈0.475). In another aspect, the weight ratio range of totalplasticizer to total polymer is about 20:40 (≈0.5). In another aspect,the weight ratio range of total plasticizer to total polymer is about19.3:40.4 (≈0.477).

In one embodiment, the solvent comprises about 20% to about 40% of theenteric soft capsule composition, including all integers within thespecified range. In one embodiment, the solvent is water. The quantityof water in the composition varies depending on the quantities of theother ingredients. For example, the quantity of opacifier, colorant,flavoring, or other excipients can change the percentage of waterpresent the composition. In one embodiment, the weight percentage ofwater is as much as suffices to bring the total weight percentage to100% (i.e., quantum sufficiat; q.s.). In another embodiment, the watercomprises about 20%, about 25%, about 30%, about 35%, or about 40% ofthe enteric soft capsule composition. In another embodiment, watercomprises about 35% to about 40% of the enteric soft capsulecomposition. In one embodiment, water comprises about 37% of thecomposition.

In one embodiment, the final moisture (water) content of the entericsoft capsule is from about 8% to about 15%, including all integerswithin the specified range. In another embodiment, the moisture contentis about 8% to about 12%, including all integers within the specifiedrange. In one aspect, the final moisture content is about 8%. In oneaspect, the final moisture content is about 9%. In one aspect, the finalmoisture content is about 10%. In one aspect, the final moisture contentis about 11%. In another aspect, the final moisture content is about12%.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 7.

TABLE 7 Exemplary Enteric Soft Capsule Shell Composition ComponentPercent weight Gelatin 29.2 Methacrylic Acid Copolymer (EUDRAGIT ® L100) 11.2 Glycerol 18.0 Triethyl citrate 1.3 Ammonium hydroxide 1.7Titanium dioxide 1.5 Water 37.1 TOTAL 100% Final pH ~4-9 Total polymer %weight (gelatin + enteric) 40.4% Gelatin % wt of total polymer(gelatin + enteric) 72.4% Enteric % wt of total polymer (gelatin +enteric) 27.6% Ratio of Enteric to Gelatin 11.2:29.2 (0.38) Totalplasticizer % weight (glycerol +triethyl citrate) 19.3% Ratio of totalplasticizer to total polymer 19.3:40.4 (0.48) Ratio total plasticizer togelatin 19.3:29.2 (0.66) Ratio total plasticizer to enteric 19.3:11.2(1.73) Water content in dried enteric soft capsule: 8-15%

In one embodiment, the enteric soft capsule shell comprises about 30%gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol;about 1% triethyl citrate; about 1.5% ammonia; about 37% water; andabout 1.5% titanium dioxide.

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft gel composition with enteric acid-insoluble properties,at relatively low concentrations of the enteric acid-insoluble polymer(e.g., from about 8% to about 20% of the total wet gel mass composition)and without the need of excessive amounts of alkali, thus avoidingdenaturation or degradation of the film-forming polymer that can weakenthe integrity of the enteric soft capsule shell.

In some embodiments, the enteric soft capsule shell does not dissolve ordisintegrate in acids, such as 0.1 N hydrochloric acid or simulatedgastric fluid (ca. pH 1.2), despite the fact that the majority of theshell ingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. In some embodiments, the enteric soft capsulesmade using the compositions described herein remain intact inhydrochloric acid or simulated gastric fluid for at least two hours andthe capsules readily release their contents upon shifting the pH of thesolution to ca. 6.8, such as that of simulated intestinal fluid. In oneaspect, the enteric soft capsule is resistant to dissolution at about pH1.2 for at least about 2 hours. In another aspect, the enteric softcapsule begins dissolution at pH of about 6.8 within about 10 min.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein can be sealed at normal temperaturerange typically used for making traditional soft gel capsules. In oneaspect, enteric soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The samethicknesses, capsule types and sizes as described herein for softcapsules can also be used for enteric soft capsules.

In another embodiment, the capsule is a soft capsule comprising afilm-forming polymer that is stable at higher temperatures (e.g., about50° C. to about 80° C.). An exemplary film-forming polymer iscarrageenan (e.g., kappa or iota carrageenan). Exemplary, non-limitingsoft capsules comprising carrageenan are described in the InternationalPatent Application Publication No. WO 2003/061633; U.S. PatentApplication Publication No. US 2004/0052839; and U.S. Pat. Nos.6,949,256 and 7,887,838, each of which is incorporated by referenceherein for such teachings. In one aspect, soft capsules comprising afilm-forming polymer stable at high temperatures allow for matrix fillshaving a higher viscosity to be encapsulated minimizing the use ofadditional plasticizers. The increased encapsulation temperature, forexample, from about 50° C. to about 80° C. allows for a viscous matrixat a lower temperature to exhibit flowability for encapsulation by themethods described herein (e.g., rotary die encapsulation).

In another embodiment, the capsule shell is a hard capsule shell. In oneaspect, the hard capsule shell may comprise the abuse deterrent matricesdescribed herein. Any hard capsule shell, for example hard capsuleshells comprising gelatin, HPMC, or pullulan, including hard capsuleshells exhibiting enteric properties, maybe used with the abusedeterrent matrix fills described herein. Hard capsule shells are knownin the art and are described by Kathpalia et al., J. Adv. Pharm. Edu. &Res. 4(2): 165-177 (2014), which is incorporated by reference herein forits specific teachings thereof.

In another embodiment, the capsule shell may be a soft capsule shellthat comprises multiple charges. The charges may be spatially separatedso that a first portion of the capsule shell has one or more charges anda second portion of the capsule shell has one or more charges. In someembodiments described herein, the ionic charges result from chargedpolymers included in the capsule shell. Thus, in some aspects, thecapsule may comprise a portion that has a positive charge and a secondportion that has a negative charge.

In one embodiment, the positive soft capsule shell comprises a typegelatin A; dimethylaminoethyl methacrylate copolymer; glycerol; HCl,water and optionally polyethylene oxide; an opacifier, colorant,flavoring, or other pharmaceutical excipient. Type A gelatins useful forthe charged soft capsule shells described herein has approximately 80millimoles of free carboxyl groups per 100 g of protein with anisoelectric point (PI) of about 7.0-9.0. Exemplary and non-limitingpolymers for use in the positive charged soft capsule shells describedherein are shown in Table 8.

In one embodiment, the negative soft capsule shell comprises a typegelatin B; methacrylic acid coploymer; glycerol; ammonium hydroxide,HCl, water and optionally polyethylene oxide; an opacifier, colorant,flavoring, or other pharmaceutical excipient. Type B gelatins useful forthe charged soft capsule shells described herein has approximately100-115 millimoles of free carboxyl groups per 100 g of protein with anisoelectric point (PI) of about 4.7-5.2. Exemplary and non-limitingpolymers for use in the positive charged soft capsule shells describedherein are shown in Table 9.

TABLE 8 Exemplary Polymers Useful for Positive Soft Capsule ShellCompositions EX 1 EX 2 EX 3 Gelatin (Type A) Gelatin (Type A) Gelatin(Type A) Iso Elec. Pt. 8.9 (From Nitta) DimethylaminoethylDimethylaminoethyl Dimethylaminoethyl Methacrylate CopolymerMethacrylate Copolymer Methacrylate (EUDRAGIT ® EPO) (EUDRAGIT ® EPO)Copolymer (EUDRAGIT ® EPO) Glycerol Glycerol Glycerol HCl HCl HCl WaterWater Water Polyethylene oxide

TABLE 9 Exemplary Polymers Useful for Negative Soft Capsule ShellCompositions EX 4 EX 5 EX 6 Gelatin (Type B) Gelatin (Type B) Gelatin(Type B) Iso Elec. Pt. 4 (From Nitta) Methacrylic Acid Methacrylic AcidIota-carrageenan Coploymer Coploymer (EUDRAGIT ® L100) (EUDRAGIT ® L100)Glycerol Glycerol Glycerol Ammonium Hydroxide Ammonium Hydroxide Water0.1N HCl 0.1N HCl Water 1% Polyethylene oxide Water

In another embodiment the multiple charged soft capsule shell may be adual charged capsule shell. As described herein, the dual charged softcapsule shell may comprise a first portion that is positively chargedand a second portion that is negatively charged. The positive portion ofthe soft capsule shell may be prepared by forming a positive gel massribbon composition. Likewise, the negative portion of the soft capsuleshell may be prepared by forming a negative gel mass ribbon composition.The two ribbon compositions may then be combined using standard rotarydie encapsulation techniques to form a dual charged (positive andnegative) total soft capsule shell. This total soft capsule shell mayfurther encapsulate one or more active pharmaceutical ingredients (e.g.,drug-resinate) in an abuse deterrent matrix as described herein.Exemplary and non-limiting dual charged soft capsule shell gel massribbon compositions are provided in Table 10.

In another embodiment, a soft capsule shell may be further coated withone or more charged film compositions according to Tables 8-10. In oneaspect, a charged soft capsule shell comprising the composition of anyone of Tables 8-10 may further be coated with an additional filmcomposition according to any one of Tables 8-10.

TABLE 10 Exemplary Dual Charged Soft Capsule Shell Gel Mass RibbonCompositions Positive Percentage Negative Percentage Components (%) (%)Gelatin 20-35   20-35 Methacrylic Acid Copolymer —   5-20 (EUDRAGIT ® L100) Dimethylaminoethyl  4-22 — Methacrylate Copolymer (EUDRAGIT ® EPO)Glycerol  5-25   5-25 Triethyl citrate 0.5-3 HCl 0.5 — Ammoniumhydroxide — 0.5-5 Titanium dioxide — 0.5-5 Water 30-50   30-50 TOTAL 100100

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a solid dosage form such as a powder or acompressed tablet. In one aspect, the composition is a non-layeredhomogeneous powder suspension. In one aspect, the composition comprisesone or more active pharmaceutical ingredients and one or moresequestering agents. In one aspect, the sequestering agent comprise oneor more ionizable polymers, including cationic, anionic polymers, orzwitterionic polymers. In one aspect, the sequestering agent is an ionexchange resin. In one aspect the one or more active pharmaceuticalingredients and one or more sequestering agents are not pre-bound (e.g.,are not a resinate complex). In one aspect, the composition comprises apowder suspension of the active pharmaceutical ingredients, thesequestering agents, and optionally, one or more pharmaceuticallyacceptable excipients.

One embodiment described herein is an oral pharmaceutical compositioncomprising (a) a solid dispersion of an active pharmaceutical ingredientor a salt thereof as described herein; (b) one or more sequesteringagents; and (c) one or more pharmaceutically acceptable excipients. Insome embodiments, the composition further comprises (d) one or morefillers (e) one or more binders, (f) one or more disintegrants, or (g)one or more lubricants. In one aspect, the filler comprises one or moreof lactose, lactose monohydrate, glucose, fructose, sucrose, sorbitol,mannitol, dicalcium phosphate dihydrate, cellulose, ethyl cellulose,methyl cellulose, microcrystalline cellulose, crospovidone, or acombination thereof. In one aspect, the disintegrant comprises one ormore of crospovidone, croscarmellose sodium, alginic acid,microcrystalline cellulose, polacrilin potassium, sodium starchglycolate, starch, pregelatinized starch, or a combination thereof. Inone aspect, the lubricant comprises one or more of magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid,talc, glyceryl behenate, or a combination thereof. In one aspect, thepharmaceutical composition comprises one or more colorants, flavorings,binders, glidants, coatings, or other pharmaceutically acceptableexcipients. In one aspect, the filler comprises microcrystallinecellulose and lactose monohydrate; the disintegrant comprisescrospovidone; and the lubricant comprises magnesium stearate.

As described herein, the pharmaceutically acceptable compositionscomprise pharmaceutically acceptable excipients, carriers, adjuvants, orvehicles, which, as used herein, includes any and all solvents,diluents, or other liquid vehicle, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds described herein, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof the embodiments described herein. Some examples of materials whichcan serve as pharmaceutically acceptable carriers include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, or potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates,waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugarssuch as lactose, glucose and sucrose; starches such as corn starch andpotato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising an active pharmaceutical ingredient or a saltthereof as described herein, and one or more pharmaceutically acceptableexcipients.

Another embodiment described herein comprises a pharmaceuticalcomposition comprising a therapeutically effective amount of an activepharmaceutical ingredient or a salt thereof as described herein, and oneor more pharmaceutically acceptable carriers or vehicles.

The compositions described herein may be administered using any amountand any route of administration effective for treating or lessening theseverity of pain or non-pain diseases described herein. The exact amountof the active pharmaceutical active ingredient(s) required will varyfrom subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularagent, its mode of administration, tolerance of the individual to theactive ingredient, and the like. The compositions described herein arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thesubject to be treated. The total daily usage of the compounds andcompositions described herein will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient including but not limited to: (a) fillers or extenders such asstarches, lactose, sucrose, glucose, mannitol, and silicic acid, (b)binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectantssuch as glycerol, (d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, (e) solution retarding agents such as paraffin,(f) absorption accelerators such as quaternary ammonium compounds, g)wetting agents such as, for example, cetyl alcohol and glycerolmonostearate, (h) absorbents such as kaolin and bentonite clay, and (i)lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

As used herein, a “disintegrant” is an excipient that hydrates apharmaceutical composition and aids in tablet dispersion. Examples ofdisintegrants include crospovidone, sodium croscarmellose, alginic acid,microcrystalline cellulose, polacrilin potassium, sodium starchglycolate, starch, pregelatinized starch, or combinations thereof.

As used herein, a “filler” is an excipient that adds bulkiness to apharmaceutical composition. Examples of fillers include lactose, lactosemonohydrate, glucose, fructose, sucrose, sorbitol, mannitol, dicalciumphosphate dihydrate, cellulose, ethyl cellulose, methyl cellulose,microcrystalline cellulose, crospovidone, or a combination thereof.

As used herein, a “binder” is an excipient that imparts a pharmaceuticalcomposition with enhanced cohesion or tensile strength (e.g., hardness).Examples of binders include dibasic calcium phosphate, sucrose, corn(maize) starch, microcrystalline cellulose, and modified cellulose(e.g., hydroxymethyl cellulose).

As used herein, a “lubricant” is an excipient that is added topharmaceutical compositions that are pressed into tablets. The lubricantaids in compaction of granules into tablets and ejection of a tablet ofa pharmaceutical composition from a die press. Examples of lubricantsinclude magnesium stearate, calcium stearate, zinc stearate, sodiumstearyl fumarate, stearic acid, talc, glyceryl behenate, or acombination thereof.

As used herein, a “glidant” is an excipient that imparts apharmaceutical composition with enhanced flow properties. Examples ofglidants include colloidal silica or talc.

As used herein, a “surfactant” is an excipient that impartspharmaceutical compositions with enhanced solubility and/or wetability.Examples of surfactants include sodium lauryl sulfate (SLS), sodiumstearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g.,Tween™), or a combination thereof.

As used herein, a “colorant” is an excipient that imparts apharmaceutical composition with a desired color. Examples of colorantsinclude commercially available pigments such as FD&C coloring agents,titanium dioxide, iron oxide, or combinations thereof.

As used herein, a “flavoring” is an excipient that imparts a flavor ortaste masking property to a pharmaceutical composition. Examples offlavorings include anethole, benzaldehyde, ethyl vanillin, menthol,methyl salicylate, monosodium glutamate, orange flower oil, peppermint,peppermint oil, peppermint spirit, rose oil, stronger rose water,thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin, orcombinations thereof.

As used herein a “coating agent” makes the dosage from smoother andeasier to swallow, controls the release rate of the active ingredient,and makes the dosage from more resistant to the environment (extendingits shelf life), or enhances the dosage form's appearance Examples ofcoating agents include sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyvinyl acetate phthalate, shellac, sucrose, titaniumdioxide, carnauba wax, microcrystalline wax, zein, or combinationsthereof.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

Another embodiment described herein is a kit for dispensing the oralpharmaceutical dosage form produced by any of the compositions or themethods described herein comprising: (a) at least one dosage formcomprising one or more active pharmaceutical ingredients or saltsthereof as described herein; (b) at least one moisture proof dispensingreceptacle comprising blister or strip packs, an aluminum blister, atransparent or opaque polymer blister with pouch, polypropylene tubes,colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; and optionally (c) an insertcomprising instructions, prescribing information, or warnings for anactive pharmaceutical ingredient comprised by the pharmaceuticalcomposition; or (d) directions for administration or anycontraindications. In one aspect described herein, the kit is useful fortreating pain or a medical condition according to any of the methodsdescribed herein.

One embodiment described herein, is a pharmaceutical compositioncomprising any of the formulations shown in the Tables or Examplesdescribed herein. Any of the components of the formulations shown in theTables or Examples can be increased, decreased, combined, recombined,switched, or removed to provide for a formulation comprising about 100%by weight.

In another embodiment, the abuse deterrent pharmaceutical compositiondescribed herein provides a dosage of an active pharmaceuticalingredient described herein for administration to a subject. The dosageform can be administered, for example, to a subject, or a subject inneed thereof. In one aspect, the subject is a mammal, or a mammal inneed thereof. In one aspect, the subject is a dog. In one aspect, thesubject is a human, or human in need thereof. In one aspect, the humanor human in need thereof is a medical patient. In one aspect, the humansubject is a child (˜0-9 years old) or an adolescent (˜10-17 years old).In one aspect, the subject is from 0 to 9 years of age. In anotheraspect, the human subject is from 10 to 17 years of age. In anotheraspect, the human subject is over 17 years of age. In another aspect,the human subject is an adult (≧18 years of age).

In one embodiment, the dosage may be administered to a human in need ofmanagement of moderate to severe chronic pain or neuropathic pain, whena continuous, persistent (around-the-clock) opioid analgesic is neededfor an extended period of time.

The dosage form can be administered, for example, 1×, 2×, 3×, 4×, 5×,6×, or even more times per day. One or more dosage form can beadministered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer.One or more dosage forms can be administered, for example, for 1, 2, 3,4 weeks, or even longer. One or more dosage forms can be administered,for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year,2, years, 3 years, 4 years, 5 years, over 5 years, a decade, multipledecades, or even longer. One or more dosage forms can be administered ata regular interval until the subject or subject in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition, including but not limited to, pain.

In one embodiment, the pharmaceutical composition described herein isadministered in multiple dosages simultaneously. For example, two ormore identical dosages are administered at one time. In anotherembodiment, two or more different dosages are administered at one time.Such dual or different simultaneous doses can be used to provide aneffective amount of the pharmaceutical composition to a subject in needthereof.

In one embodiment, the abuse deterrent oral composition describedherein, comprises one or more active pharmaceutical ingredients in anamount of about 1 mg, about 2, mg, about 3 mg, about 4 mg, about 5 mg,about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490mg, about 495 mg, about 500 mg, about 510 mg, about 520 mg, about 530mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980mg, about 990 mg, about 1000 mg, or even more. Multiples of any of theforgoing quantities can be dispensed to achieve the therapeutic effect.

In another embodiment, the compositions described herein, comprise oneor more active pharmaceutical ingredients in the range of about 20 mg toabout 250 mg, about 30 mg to about 250 mg, about 40 mg to about 250 mg,about 50 mg to about 250 mg, about 60 mg to about 250 mg, about 70 mg toabout 250 mg, about 80 mg to about 250 mg, about 90 mg to about 250 mg,about 100 mg to about 250 mg, about 110 mg to about 250 mg, about 120 mgto about 250 mg, about 130 mg to about 250 mg, about 140 mg to about 250mg, about 150 mg to about 250 mg, about 160 mg to about 250 mg, about170 mg to about 250 mg, about 180 mg to about 250 mg, about 190 mg toabout 250 mg, about 200 mg to about 250 mg, about 210 mg to about 250mg, about 220 mg to about 250 mg, about 230 mg to about 250 mg, about240 mg to about 250 mg; about 250 mg to about 500 mg, about 260 mg toabout 500 mg, about 270 mg to about 500 mg, about 280 mg to about 500mg, about 290 mg to about 500 mg, about 300 mg to about 500 mg, about310 mg to about 500 mg, about 320 mg to about 500 mg, about 330 mg toabout 500 mg, about 340 mg to about 500 mg, about 350 mg to about 500mg, about 360 mg to about 500 mg, about 370 mg to about 500 mg, about380 mg to about 500 mg, about 390 mg to about 500 mg, about 400 mg toabout 500 mg, about 410 mg to about 500 mg, about 420 mg to about 500mg, about 430 mg to about 500 mg, about 440 mg to about 500 mg, about450 mg to about 500 mg, about 460 mg to about 500 mg, about 470 mg toabout 500 mg, about 480 mg to about 500 mg, or about 490 mg to about 500mg. Multiples of any of the forgoing quantities can be dispensed toachieve the therapeutic effect.

In one embodiment described herein, the compositions described hereinmay comprise an active pharmaceutical ingredient load (e.g., a drug loadof one or more active pharmaceutical ingredients) of about 1% to about90%, including each integer within the specified range. In oneembodiment, the drug load can comprise about 1%, about 2%, about 2.5%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or even higher.In one aspect, the drug load is about 5%. In one aspect, the drug loadis about 10%. In one aspect, the drug load is about 20%. In one aspect,the drug load is about 25%. In one aspect, the drug load is about 30%.In one aspect, the drug load is about 33%. In one aspect, the drug loadis about 35%. In one aspect, the drug load is about 40%. In one aspect,the drug load is about 50%. In one aspect, the drug load is about 60%.In one aspect, the drug load is about 17%. In one aspect, the drug loadis about 15%. In one aspect, the drug load is about 12%. In oneembodiment, the drug load is about 50%.

In one embodiment, the active pharmaceutical ingredient is oxycodone,hydrocodone or codeine, or a salt, ether, ester, variant, or derivativethereof. In one embodiment, the active pharmaceutical ingredient isoxycodone. In another embodiment, the active pharmaceutical ingredientis hydrocodone. See Prescribing Information for OxyContin® ER 04/2014(Purdue Pharma LP; available at www.purduepharma.com) and Zohydro® ER01/2015 (Zogenix® Inc. available at: www.zogenix.com), which areincorporated by reference herein for such teachings.

In another embodiment, the active pharmaceutical ingredient may compriseoxycodone, hydrocodone, or codeine and an additional activepharmaceutical ingredient. In one aspect, the additional activepharmaceutical ingredient prevents opioid abuse when an excess of opioidis used. In another aspect, the additional active pharmaceuticalingredient reduces or prevents opioid induced side effects.

In one embodiment, the abuse deterrent oral composition described hereincomprises a dose of hydrocodone. In one aspect, the dose of hydrocodoneis about 5 mg. In one aspect, the dose of hydrocodone is about 10 mg. Inone aspect, the dose of hydrocodone is about 20 mg. In another aspect,the dose of hydrocodone is about 30 mg. In another aspect, the dose ofhydrocodone is about 40 mg. In another aspect, the dose of hydrocodoneis about 50 mg. In another aspect, the dose of hydrocodone is about 60mg. In another aspect, the dose of hydrocodone is about 70 mg. Inanother aspect, the dose of hydrocodone is about 80 mg. In anotheraspect, the dose of hydrocodone is about 90 mg. In another aspect, thedose of hydrocodone is about 100 mg. In another aspect, the dose ofhydrocodone is about 120 mg. In another aspect, the dose of hydrocodoneis about 140 mg. In another aspect, the dose of hydrocodone is about 160mg. In another aspect, the dose of hydrocodone is about 180 mg. Inanother aspect, the dose of hydrocodone is about 200 mg.

In one embodiment, the abuse deterrent oral composition described hereincomprises a dose of oxycodone. In one aspect, the dose of oxycodone isabout 5 mg. In another aspect, the dose of oxycodone is about 10 mg. Inanother aspect, the dose of oxycodone is about 15 mg. In another aspect,the dose of oxycodone is about 20 mg. In another aspect, the dose ofoxycodone is about 30 mg. In another aspect, the dose of oxycodone isabout 40 mg. In another aspect, the dose of oxycodone is about 50 mg. Inanother aspect, the dose of oxycodone is about 60 mg. In another aspect,the dose of oxycodone is about 70 mg. In another aspect, the dose ofoxycodone is about 80 mg. In another aspect, the dose of oxycodone isabout 100 mg. In another aspect, the dose of oxycodone is about 120 mg.In another aspect, the dose of oxycodone is about 140 mg. In anotheraspect, the dose of oxycodone is about 160 mg. In another aspect, thedose of oxycodone is about 180 mg. In another aspect, the dose ofoxycodone is about 200 mg.

In another embodiment, the total dosage of oxycodone or hydrocodoneadministered in a 24-hour period is about 20 mg to about 600 mg per24-hour period. In one aspect, the total dosage of oxycodone orhydrocodone administered in a 24-hour period is about 50 mg to about 250mg per 24-hour period. The dosage can contain a total amount ofoxycodone or hydrocodone effective for treatment, amelioration,prophylaxis, or reducing the onset of or symptoms of pain.

In one embodiment, the recommended dosage is based upon the condition ofthe subject in need thereof. The subject can comprise a human or mammalin need thereof. In one aspect, the need is defined as a painfulcondition or perception of pain. In one embodiment, the initial dosageof hydrocodone is 10 mg to about 40 mg. In one aspect, an initial doseof about 10 mg to about 40 mg is suitable for a subject that nottolerant of an opioid. In one aspect, the initial dose is about 10 mg ofhydrocodone. In another aspect, the initial dose is about 20 mg ofhydrocodone. In another aspect, the initial dose is about 20 mg ofhydrocodone. In another aspect, the initial dose is about 30 mg ofhydrocodone. In another aspect, the initial dose is about 40 mg ofhydrocodone. In another aspect, the dose of hydrocodone may bemaintained and given every 8 to 12 hours. In another aspect, the dose ofhydrocodone may be increased by about 10 mg to about 20 mg every 8 hrsto 12 hrs until relief of a painful condition or the perception of painoccurs.

In another embodiment, the initial dosage of hydrocodone is 40 mg toabout 80 mg. In one aspect, an initial dose of about 40 mg to about 80mg is suitable for a subject that has an opioid tolerant phenotype. Inone aspect, the initial dose is about 40 mg of hydrocodone. In anotheraspect, the initial dose is about 50 mg of hydrocodone. In anotheraspect, the initial dose is about 60 mg of hydrocodone. In anotheraspect, the initial dose is about 70 mg of hydrocodone. In anotheraspect, the initial dose is about 80 mg of hydrocodone. In anotheraspect, the dose of hydrocodone may be maintained and given every 8 to12 hours. In another aspect, the dose of hydrocodone may be increased byabout 10 mg to about 20 mg every 8 hrs to 12 hrs until relief of apainful condition or the perception of pain occurs.

In one embodiment, the recommended dosage is based upon the condition ofthe subject in need thereof. The subject can comprise a human or mammalin need thereof. In one aspect, the need is defined as a painfulcondition or perception of pain. In one embodiment, the initial dosageof oxycodone is 10 mg to about 40 mg. In one aspect, an initial dose ofabout 10 mg to about 40 mg is suitable for a subject that not tolerantof an opioid and a dose. In one aspect, the initial dose is about 10 mgof oxycodone. In another aspect, the initial dose is about 20 mg ofoxycodone. In another aspect, the initial dose is about 20 mg ofoxycodone. In another aspect, the initial dose is about 30 mg ofoxycodone. In another aspect, the initial dose is about 40 mg ofoxycodone. In another aspect, the dose of oxycodone may be maintainedand given every 8 to 12 hours. In another aspect, the dose of oxycodonemay be increased by about 10 mg to about 20 mg every 8 hrs to 12 hrsuntil relief of a painful condition or the perception of pain occurs.

In another embodiment, the initial dosage of oxycodone is 40 mg to about160 mg. In one aspect, an initial dose of about 40 mg to about 80 mg issuitable for a subject that has an opioid tolerant phenotype. In oneaspect, the initial dose is about 40 mg of oxycodone. In another aspect,the initial dose is about 50 mg of oxycodone. In another aspect, theinitial dose is about 60 mg of oxycodone. In another aspect, the initialdose is about 70 mg of oxycodone. In another aspect, the initial dose isabout 80 mg of oxycodone. In another aspect, the initial dose is about100 mg of oxycodone. In another aspect, the initial dose is about 120 mgof oxycodone. In another aspect, the initial dose is about 140 mg ofoxycodone. In another aspect, the initial dose is about 160 mg ofoxycodone. In another aspect, the dose of oxycodone may be maintainedand given every 8 to 12 hours. In another aspect, the dose of oxycodonemay be increased by about 10 mg to about 20 mg every 8 hrs to 12 hrsuntil relief of a painful condition or the perception of pain occurs.

Additional pain that the abuse deterrent pharmaceutical compositiondescribed herein may be useful for the treatment of pain stemming fromincluding, but not limited to, chronic arthritis, osteoarthritis,rheumatoid arthritis, acute tendonitis, bursitis, headaches, migraines,chronic neuropathies, shingles, premenstrual symptoms, sports injuries,malignancy, radiculopathy, sciatica/sciatic pain, sarcoidosis,necrobiosis, lipoidica, or granuloma annulare.

In another embodiment, the abuse deterrent pharmaceutical compositioncomprising an abuse deterrent composition as described herein reducesthe dissolution and extraction of an active pharmaceutical ingredient.Suitable non-limiting examples of extraction methods comprise incubatingthe abuse deterrent pharmaceutical composition in boiling conditions, inaqueous solutions of alcohol, and in distilled water. These methods maybe used in conjunction with additional means of agitating, for example,with paddles, dipping, vigourous shaking, physical manipulations, andthe like.

Another embodiment described herein is an abuse deterrent pharmaceuticalcomposition as described herein comprising a therapeutically effectiveamount of one or more active pharmaceutical ingredients foradministration to a subject having pain, exhibiting an in vitrodissolution rate as described herein in any one of FIGS. 3-17.

Another embodiment described herein is a method for orally administeringa dosage form of an abuse deterrent pharmaceutical compositioncomprising an active pharmaceutical ingredient described herein for thetreatment, amelioration, prophylaxis, or reducing the onset of orsymptoms of pain.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of pain, comprising administering to asubject in need thereof an oral pharmaceutical composition as describedherein comprising a therapeutically effective amount of one or moreactive pharmaceutical ingredients for administration to a subject havingpain, exhibiting an in vitro dissolution rate as described herein in anyone of FIGS. 3-17.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of oxycodone to about 80 mg ofoxycodone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone C_(max) of about 10 ng/mL to about 150 ng/mL, includingeach integer within the specified range. In one aspect, the compositionis provided in a dosage form containing a total amount of about 10 mg ofoxycodone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone C_(max) of about 10 ng/mL. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 20 mg of oxycodone, wherein subjects administered a single dosageexhibit a mean plasma oxycodone C_(max) of about 20 ng/mL. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of oxycodone, wherein subjects administered asingle dosage exhibit a mean plasma oxycodone C_(max) of about 40 ng/mL.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg of oxycodone, wherein subjectsadministered a single dosage exhibit a mean plasma oxycodone C_(max) ofabout 100 ng/mL.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of oxycodone to about 80 mg ofoxycodone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone AUC_(0→∝) of about 100 h·mg/L to about 1000 h·mg/L,including each integer within the specified range. In one aspect, thecomposition is provided in a dosage form containing a total amount ofabout 10 mg of oxycodone, wherein subjects administered a single dosageexhibit a mean plasma oxycodone AUC_(0→∝) of about 100 h·mg/L. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 20 mg of oxycodone, wherein subjectsadministered a single dosage exhibit a mean plasma oxycodone AUC_(0→∝)of about 200 h·mg/L. In another aspect, the composition is provided in adosage form containing a total amount of about 40 mg of oxycodone,wherein subjects administered a single dosage exhibit a mean plasmaoxycodone AUC_(0→∝) of about 400 h·mg/L. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 80 mg of oxycodone, wherein subjects administered a single dosageexhibit a mean plasma oxycodone AUC_(0→∝) of about 1000 h·mg/L.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of oxycodone to about 80 mg ofoxycodone, wherein subjects administered a single dosage exhibits aT_(max) of about 1 hr to about 8 hrs, including each integer within thespecified range. In one aspect, the composition is provided in a dosageform containing a total amount of about 10 mg to about 80 mg ofoxycodone, wherein subjects administered a single dosage exhibit aT_(max) of about 1 hr, about 1.5 hrs, about 2 hrs, about 2.5 hrs, about3 hrs, about 3.5 hrs, about 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5hrs, 7 hrs, 7.5 hrs, or about 8 hrs.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of hydrocodone to about 80 mg ofhydrocodone, wherein subjects administered a single dosage exhibit amean plasma hydrocodone C_(max) of about 10 ng/mL to about 120 ng/mL,including each integer within the specified range. In one aspect, thecomposition is provided in a dosage form containing a total amount ofabout 10 mg of a hydrocodone, wherein subjects administered a singledosage exhibit a mean plasma hydrocodone C_(max) of about 20 ng/mL. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 20 mg of hydrocodone, wherein subjectsadministered a single dosage exhibit a mean plasma hydrocodone C_(max)of about 30 ng/mL. In another aspect, the composition is provided in adosage form containing a total amount of about 30 mg of hydrocodone,wherein subjects administered a single dosage exhibit a mean plasmahydrocodone C_(max) of about 40 ng/mL. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 40 mg of hydrocodone, wherein subjects administered a singledosage exhibit a mean plasma hydrocodone C_(max) of about 60 ng/mL. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 80 mg of hydrocodone, wherein subjectsadministered a single dosage exhibit a mean plasma hydrocodone C_(max)of about 120 ng/mL.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of hydrocodone to about 80 mg ofhydrocodone, wherein subjects administered a single dosage exhibit amean plasma hydrocodone AUC_(0→∝) of about 100 h·mg/L to about 1600h·mg/L, including each integer within the specified range. In oneaspect, the composition is provided in a dosage form containing a totalamount of about 10 mg of a hydrocodone, wherein subjects administered asingle dosage exhibit a mean plasma hydrocodone AUC_(0→∝) of about 150h·mg/L. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 20 mg of hydrocodone, whereinsubjects administered a single dosage exhibit a mean plasma hydrocodoneAUC_(0→∝) of about 400 h·mg/L. In another aspect, the composition isprovided in a dosage form containing a total amount of about 40 mg ofhydrocodone, wherein subjects administered a single dosage exhibit amean plasma hydrocodone AUC_(0→∝) of about 850 h·mg/L. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 80 mg of hydrocodone, wherein subjects administered asingle dosage exhibit a mean plasma hydrocodone AUC_(0→∝) of about 1600h·mg/L.

Another embodiment described herein is a method for treating anindividual having pain, with a pharmaceutical composition describedherein comprising an abuse deterrent composition described hereincomprising a dosage of about 10 mg of hydrocodone to about 80 mg ofhydrocodone, wherein subjects administered a single dosage exhibits aT_(max) of about 3 hrs to about 8 hrs, including each integer within thespecified range. In one aspect, the composition is provided in a dosageform containing a total amount of about 10 mg to about 80 mg ofhydrocodone, wherein subjects administered a single dosage exhibit aT_(max) of about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7hrs, or about 8 hrs.

In another embodiment, the pharmaceutical compositions described hereinfurther comprise one or more active pharmaceutical ingredient(s)suitable for treating, ameliorating, or prophylactically treating abowel dysfunction due to acute or chronic opioid use, often referred toas opioid induced bowel disfunction (OIBD). Symptoms of OIBD typicallycomprise constipation (e.g., opioid induced constipation; OIC),anorexia, nausea and vomiting, gastro-oesophageal reflux, delayeddigestion, abdominal pain, flatulence, bloating, hard stools, incompleteevacuation or straining during bowel movements. Alternative oradditional uses for the one or more active pharmaceutical ingredient(s)described herein may be to treat, reduce, inhibit, or prevent additionaleffects of acute or chronic opioid use including, e.g., aberrantmigration or proliferation of endothelial cells (e.g., vascularendothelial cells), increased angiogenesis, and increase in lethalfactor production from opportunistic infectious agents (e.g.,Pseudomonas aeruginosa). Additional advantageous uses of one or moreactive pharmaceutical ingredient(s) include treatment of opioid-inducedimmune suppression, inhibition of angiogenesis, inhibition of vascularproliferation, treatment of pain, treatment of inflammatory conditionssuch as inflammatory bowel syndrome, treatment of infectious diseasesand diseases of the musculoskeletal system such as osteoporosis,arthritis, osteitis, periostitis, myopathies, and treatment ofautoimmune diseases, terminally ill patients receiving opioid therapysuch as an AIDS patient, a cancer patient, a cardiovascular patient;subjects receiving opioid therapy for maintenance of opioid withdrawal.In one aspect, the subject is a subject using an opioid for chronic painmanagement. In another aspect, the subject is a subject using an acutelyusing an opioid for temporary pain management. In another aspect, thesubject is a terminally ill patient. In another aspect, the subject is aperson receiving opioid withdrawal maintenance therapy.

In another embodiment, suitable active pharmaceutical ingredients fortreating a symptom or condition of opioid use may comprise a laxativesuch as lubiprostone, linaclotide, lactulose, and a heavy molecularweight poly ethylene glycol (e.g., PEG 3350; Miralax®; GlycoLax),sorbitol, calcium carbonate, potassium phosphate, magnesium hydroxide,psyllium, glycerin, polycarbophil, or docusate, or a mixture orcombination thereof. In some aspects, other suitable pharmaceuticalingredients may comprise a natural therapeutic or nutraceuticalcomprising barberry, cascara sagrada, flax, or senna or a mixture orcombination thereof. In some further aspects, suitable activepharmaceutical ingredients for the treatment, amelioration, orprophylaxis of OIBD or OIC comprise a peripherally acting mu-opioidreceptor antagonist (PAMORA). In some aspects, the PAMORA comprisesmethylnaltrexone, naltrexone, naloxone, naloxegol, or alvimopan, or amixture or combination thereof.

It is understood that activation of mu-opiod receptors along the gastrointestinal tract are responsible for decreased bowel function andconstipation. Thus, without being bound by any theory, PAMORAs areuseful for preventing symptoms of OIBD, and specifically OIC, byinhibiting the action of the mu-opioid receptor peripherally along thegastro-intestinal tract without inhibiting the mu-opiod receptors of thecentral nervous system (CNS). Therefore, a combination of an opioidagonist (e.g., oxycodone or hydrocodone) activates the CNS receptors andthe co-administration of a PAMORA inhibits the peripheral gut mu-opioidreceptors, which are believed to be responsible for the incurrence ofOIC.

In one embodiment, the pharmaceutical compositions described hereincomprise a dose of an opioid (e.g., oxycodone or hydrocodone) and a doseof a PAMORA. In one aspect, the pharmaceutical compositions describedherein comprise a dose of an opioid and a dose of a PAMORA comprisingnaloxone or a pharmaceutically acceptable salt form thereof. In oneaspect, the pharmaceutical compositions described herein comprise a doseof an opioid and a dose of a PAMORA comprising naltrexone or apharmaceutically acceptable salt form thereof. In another aspect, thepharmaceutical compositions described herein comprise a dose of anopioid and a dose of a PAMORA comprising methylnaltrexone or apharmaceutically acceptable salt form thereof. In another aspect, thepharmaceutical compositions described herein comprise a dose of anopioid and a dose of a PAMORA comprising naloxegol or a pharmaceuticallyacceptable salt form thereof.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of a PAMORA (e.g., naloxegol, naloxone,methylnaltrexone, or naltrexone) and a dose of an opioid (e.g.,hydrocodone or oxycodone). In one aspect, the dose of the PAMORA rangesfrom about 50 mg to about 600 mg and the dose of the opioid is fromabout 5 mg to about 150 mg, including every integer within the specifiedranges. In another aspect, the dose of the PAMORA ranges from about 50mg to about 550 mg and the dose of the opioid is from about 5 mg toabout 150 mg, including every integer within the specified ranges. Inanother aspect, the dose of the PAMORA ranges from about 5 mg to about50 mg and the dose of the opioid is from about 5 mg to about 100 mg,including every integer within the specified ranges.

In another embodiment, the weight percentage ratio range of PAMORA(e.g., naloxegol, naloxone, methylnaltrexone, or naltrexone) to opioid(e.g., hydrocodone or oxycodone) in the pharmaceutical compositiondescribed herein ranges from about 15:1 to about 1:18, including eachratio within the specified range. In one aspect, the weight percentageratio range of PAMORA (e.g., naloxegol, naloxone, methylnaltrexone, ornaltrexone) to opioid is from about 13:1 to about 1:1, including eachratio within the specified range. In another aspect, the weightpercentage ratio range of PAMORA (e.g., naloxegol, naloxone,methylnaltrexone, or naltrexone) to opioid is from about 1:16 to about1:1, including each ratio within the specified range. In another aspect,the weight percentage ratio range of PAMORA to opioid is about 1:16,about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10,about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1,about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1,about 12:1, about 13:1, about 14:1, or about 15:1.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of naloxone and a dose of an opioid comprisinghydrocodone or oxycodone as described herein. In one aspect, the dose ofthe naloxone ranges from about 2.5 mg to about 100 mg, including eachinteger within the specified range. In another aspect, the dose ofnaloxone ranges from about 2.5 mg to about 50 mg, including each integerwithin the specified range. In another aspect, the dose of naloxoneranges from about 10 mg to about 50 mg, including each integer withinthe specified range. In another aspect, the dose of naloxone ranges fromabout 20 mg to about 40 mg, including each integer within the specifiedrange. In another aspect, the dose of naloxone is about 2.5 mg, about 5mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In another embodiment, the weight percentage ratio range of naloxone toopioid comprising hydrocodone or oxycodone in the pharmaceuticalcomposition described herein ranges from about 1:10 to about 5:1,including all iterations of ratios within the specified range. In oneaspect, the weight percentage ratio range of naloxone to opioidcomprising hydrocodone or oxycodone is from about 1:5 to about 1:1,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of naloxone to opioidcomprising hydrocodone or oxycodone is from about 1:4 to about 1:2,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of naloxone to opioidcomprising hydrocodone or oxycodone is about 1:10, about 1:9, about 1:8,about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about1:1, about 2:1, about 3:1, about 4:1, or about 5:1. In another aspect,the weight percentage ratio range of naloxone to opioid comprisinghydrocodone or oxycodone is about 1:2.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 5 mg of naloxone and a dose of about 10 mg ofoxycodone. In another embodiment, the pharmaceutical compositiondescribed herein comprises a dose of about 10 mg of naloxone and a doseof about 20 mg of oxycodone. In another embodiment, the pharmaceuticalcomposition described herein comprises a dose of about 20 mg of naloxoneand a dose of about 40 mg of oxycodone. In another embodiment, thepharmaceutical composition described herein comprises a dose of about 40mg of naloxone and a dose of about 80 mg of oxycodone. In anotherembodiment, the pharmaceutical composition described herein comprises adose of about 80 mg of naloxone and a dose of about 160 mg of oxycodone.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 5 mg of naloxone and a dose of about 10 mg ofhydrocodone. In another embodiment, the pharmaceutical compositiondescribed herein comprises a dose of about 10 mg of naloxone and a doseof about 20 mg of hydrocodone. In another embodiment, the pharmaceuticalcomposition described herein comprises a dose of about 20 mg of naloxoneand a dose of about 40 mg of hydrocodone. In another embodiment, thepharmaceutical composition described herein comprises a dose of about 40mg of naloxone and a dose of about 80 mg of hydrocodone. In anotherembodiment, the pharmaceutical composition described herein comprises adose of about 80 mg of naloxone and a dose of about 160 mg ofhydrocodone.

In another embodiment, the pharmaceutical composition described hereincomprises a dose of about 40 mg of oxycodone and a dose of about 20 mgof naloxone. In one aspect, the composition is provided in a dosage formcontaining a total amount of about 40 mg of oxycodone and about 20 mg ofnaloxone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone AUC_(0→∝) of about 400 h·mg/L to about 600 h·mg/L and amean plasma naloxone AUC_(0→∝) of about 500 h·mg/L to about 600 h·mg/L.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 40 mg of oxycodone and about 20 mg ofnaloxone, wherein subjects administered a single dosage exhibit a meanplasma oxycodone C_(max) of about 30 ng/mL to about 50 ng/mL and a meanplasma naloxone C_(max) of about 50 ng/mL to about 70 ng/mL. In anotheraspect, the composition is provided in a dosage form containing a totalamount of about 40 mg of oxycodone and about 20 mg of naloxone, whereinsubjects administered a single dosage exhibit an oxycodone T_(max) ofabout 1 hr to about 5 hrs and a naloxone T_(max) of about 0.5 hr toabout 3 hrs.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of methylnaltrexone or naltrexone and a dose of anopioid comprising hydrocodone or oxycodone as described herein. In oneaspect, the dose of the methylnaltrexone or naltrexone ranges from about2.5 mg to about 100 mg, including each integer within the specifiedrange. In another aspect, the dose of methylnaltrexone or naltrexoneranges from about 50 mg to about 600 mg, including each integer withinthe specified range. In another aspect, the dose of methylnaltrexone ornaltrexone ranges from about 100 mg to about 600 mg, including eachinteger within the specified range. In another aspect, the dose ofmethylnaltrexone or naltrexone ranges from about 300 mg to about 600 mg,including each integer within the specified range. In another aspect,the dose of methylnaltrexone or naltrexone ranges from about 400 mg toabout 600 mg, including each integer within the specified range. Inanother aspect, the dose of methylnaltrexone or naltrexone is about 50mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,about 450 mg, about 475 mg, about 500 mg, about 525 mg, or about 550 mg.

In another embodiment, the weight percentage ratio range ofmethylnaltrexone or naltrexone to opioid comprising hydrocodone oroxycodone in the pharmaceutical composition described herein ranges fromabout 13:1 to about 1:1, including all iterations of ratios within thespecified range. In one aspect, the weight percentage ratio range ofmethylnaltrexone or naltrexone to opioid comprising hydrocodone oroxycodone is from about 10:1 to about 1:1, including all iterations ofratios within the specified range. In another aspect, the weightpercentage ratio range of methylnaltrexone or naltrexone to opioidcomprising hydrocodone or oxycodone is from about 5:1 to about 1:1,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of methylnaltrexone ornaltrexone to opioid comprising hydrocodone or oxycodone is about 1:1,about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about8:1, about 9:1, about 10:1, about 11:1, about 12:1, or about 13:1.

In one embodiment, the pharmaceutical composition described hereincomprises a dose of naloxegol and a dose of an opioid comprisinghydrocodone or oxycodone as described herein. In one aspect, the dose ofthe naloxegol ranges from about 2.5 mg to about 100 mg, including eachinteger within the specified range. In another aspect, the dose ofnaloxegol ranges from about 2.5 mg to about 50 mg, including eachinteger within the specified range. In another aspect, the dose ofnaloxegol ranges from about 10 mg to about 50 mg, including each integerwithin the specified range. In another aspect, the dose of naloxegolranges from about 20 mg to about 40 mg, including each integer withinthe specified range. In another aspect, the dose of naloxegol is about2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In another embodiment, the weight percentage ratio range of naloxegol toopioid comprising hydrocodone or oxycodone in the pharmaceuticalcomposition described herein ranges from about 1:10 to about 5:1,including all iterations of ratios within the specified range. In oneaspect, the weight percentage ratio range of naloxegol to opioidcomprising hydrocodone or oxycodone is from about 1:5 to about 1:1,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of naloxegol to opioidcomprising hydrocodone or oxycodone is from about 1:4 to about 1:2,including all iterations of ratios within the specified range. Inanother aspect, the weight percentage ratio range of naloxegol to opioidcomprising hydrocodone or oxycodone is about 1:10, about 1:9, about 1:8,about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about1:1, about 2:1, about 3:1, about 4:1, or about 5:1. In another aspect,the weight percentage ratio range of naloxegol to opioid comprisinghydrocodone or oxycodone is about 1:2.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of pain comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein to a subject with pain,wherein the administration is sufficient to achieve a reduction painrelative to baseline in the subject without substantially inducing oneor more side effects including, but not limited to, headache, vertigo,somnolence, nausea, constipation, vomiting, xerostomia, fatigue,pruritus, eructation, heartburn, abdominal discomfort, or loss ofappetite.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of pain comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein to a subject with pain,wherein the administration is sufficient to achieve a reduction painrelative to baseline in the subject without substantially inducing oneor more side effects including, but not limited to, opioid use, such as,for example, opioid induced bowel dysfunction, opioid inducedconstipation, gastrointestinal dysfunction (e.g., inhibition ofintestinal motility, constipation, GI sphincter constriction), nausea,emesis (vomiting), biliary spasm, colic, dysphoria, pruritus, urinaryretention, depression of respiration, papillary constriction,cardiovascular effects, chest wall rigidity and cough suppression,depression of stress response, and immune suppression associated withuse of narcotic analgesia, etc, or combinations thereof.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, irritable bowel syndrome, colitis,post-operative or postpartum ileus, nausea and/or vomiting, decreasedgastric motility and emptying, inhibition of the stomach, and smalland/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, idiopathicconstipation, post-operative gastrointestinal dysfunction followingabdominal surgery (e.g., colectomy (e.g., right hemicolectomy, lefthemicolectomy, transverse hemicolectomy, colectomy takedown, lowanterior resection)), and delayed absorption of orally administeredmedications or nutritive substances comprising the administration of atherapeutically effective amount of one or more abuse deterrentpharmaceutical compositions described herein.

Another embodiment described herein is a method for improving thequality of life of subjects receiving opioids, as well as to reducecomplications arising from chronic constipation, such as hemorrhoids,appetite suppression, mucosal breakdown, sepsis, colon cancer risk, andmyocardial infarction comprising the administration of a therapeuticallyeffective amount of one or more abuse deterrent pharmaceuticalcompositions described herein.

In another embodiment, the pharmaceutical composition described hereinprovides for a dosage form, which comprises an opioid and a PAMORA asdescribed in, which in terms of efficacy, is ranked good or very good bymore than 50% of patients, 60%, 70%, 80%, 90% or more of patients. Inaspect, the dosage form is provided which comprises an opioid and aPAMORA as described in, which in terms of tolerability, is ranked goodor very good by more than 50% of patients, 60%, 70%, 80%, 90% or more ofpatients.

In another embodiment, the pharmaceutical composition described hereinprovides for a dosage form, which comprises an opioid and a PAMORA asdescribed in, which provides a reduction of days with laxative intake byat least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90%. In oneaspect, the dosage form completely reduces the need for laxative to betaken independently.

In some embodiments, bowel function is assessed by observing parametersthat are associated with bowel function. In particular, bowel functionmay be determined based on parameters selected from ease or difficultyof defecation, feeling of incomplete bowel evacuation, and/or personaljudgment of patient regarding constipation. Other parameters which maybe observed alternatively or in addition in order to assess the bowelfunction of a patient include among other things stool frequency, stoolconsistency, cramping, and painful laxation. Bowel function may beassessed by measuring parameters, which are associated with bowelfunction using numerical analog scales (NAS) for these parametersbecause this may provide more accurate results. This approach isparticularly advantageous when assessing the bowel function in patientsreceiving treatment with analgesics, because analgesic efficacy of drugsis usually assessed using a numeric analog scale.

In some embodiments, a pharmaceutical composition is provided comprisingan opioid and PAMORA as described herein to provide an improvement ofthe bowel function characterized by an improvement of the mean bowelfunction score of at least 5, at least about 8, at least about 10 or atleast about 15 after administration at steady state or of a single doseto human patients or healthy human subjects, wherein the mean bowelfunction score is measured with a numerical analog scale ranging from 0to 100.

In one embodiment, the bowel function is assessed by the bowel functionindex (BFI), which is measured in patients. The mean bowel functionscore may be determined by a method for assessing bowel function in apatient comprising the steps of: providing the patient with a numericanalog scale for at least one parameter, which parameter is associatedwith bowel function; causing the patient to indicate on the numericanalog scale the amount and/or intensity of the parameter beingexperienced; and observing the amount and/or intensity of the at leastone parameter indicated on the numeric analog scale in order to assessbowel function. In one aspect the patient indicates the amount and/orintensity of parameter being experienced during the last days or weeks,e.g. during the last 1, 2, 3, 4, 5, 6, 7, 10, or 14 days. In anotheraspect, the numerical analog scale on which the patient indicateshis/her subjective experience of the observed parameter may have anysize or form and may range from 0 or any other number to any number,such as from 0 to 10 or from 0 to 50 or from 0 to 300 or from 1 to 10.In another embodiment, if more than one parameter is observed, a meanbowel function may be obtained in form of a numerical value. Thisnumerical value is the mean of the parameters observed, e.g., the threenumeric analog scale values for ease or difficulty of defecation,feeling of incomplete bowel evacuation and judgment of constipation. Theparameters, which are measures of bowel function or which are associatedwith bowel function, may comprise opioid induced bowel dysfunctions(OIBD or OIC) as described herein.

In another embodiment, bowel function may be determined based on thefollowing parameters: ease or difficulty of defecation, for exampleduring the last 7 days according to the patient assessment, wherein 0corresponds to no difficulties and 100 corresponds to severedifficulties; feeling of incomplete bowel evacuation, for example duringthe last 7 days according to the patient assessment, wherein 0corresponds to no feeling of incomplete bowel evacuation and 100corresponds to very strong feeling of incomplete bowel evacuation;personal judgment of patient regarding constipation, for example duringthe last 7 days, wherein 0 corresponds to no constipation at all and 100corresponds to very heavy constipation.

In another embodiment, bowel function may be assessed with analogsscales as described in U.S. Pat. No. 6,258,042 and International PatentApplication Publication No. WO 2003/073937, which may be adapted todevices or analog scales as described above as would be understood byone of ordinary skill in the art. The disclosures of these tworeferences are hereby incorporated by reference for such teachings.

In another embodiment, the pharmaceutical compositions described hereinfurther comprise one or more active pharmaceutical ingredient(s), whichprevent drug abuse by inhibiting the action or effects of an opioid. Inone aspect, the pharmaceutical composition comprises an opioid (e.g.,hydrocodone or oxycodone) and one or more abuse deterrent aversiveagents. The abuse deterrent aversive agent may be any one of a laxativesuch as lubiprostone, linaclotide, lactulose, and a heavy molecularweight poly ethylene glycol (e.g., PEG 3350; Miralax®; GlycoLax),sorbitol, calcium carbonate, potassium phosphate, magnesium hydroxide,psyllium, glycerin, polycarbophil, or docusate, or a mixture orcombination thereof. Further abuse deterrent aversive agents maycomprise methylnaltrexone, naltrexone, naloxone, naloxegol, oralvimopan, or a mixture or combination thereof. The aversive effect ofthe abuse deterrent aversive agent may include any unpleasant sideeffect comprising inducing opioid withdrawl symptoms, diarrhea, nausea,reduced euphoria or a mixture or combination thereof.

In another embodiment, the abuse deterrent pharmaceutical compositiondescribed herein is contained and dispensed from a tamper evidentpackaging. The term “tamper evident” or “tamper resistant” refers to apackaging of any kind that readily displays or allows for an individualto observe any physical interference or manipulation of the packaging.The tamper evident packaging provides reasonable evidence to consumersthat tampering has occurred. The tamper evident packaging additionallycontains appropriate labelling statements describing the features andevidences of the tamper evident packaging. In one aspect, the tamperevident packaging comprises: bottles, film wrappers, blister or strippacks, bubble packs, heat shrink bands or wrappers, foil, paper, orplastic pouches, container mouth inner seals, tape seals, breakablecaps, sealed metal tubes or plastic heat-sealed tubes, sealed cartons,aerosol containers, cans including metal and composite materials, or anycombination thereof. The packaging may also contain appropriateinstructions for prescribing, instructions for use, contraindications,warnings, or other appropriate information.

It will be apparent to one of ordinary skill in the relevant art thatsuitable modifications and adaptations to the compositions,formulations, methods, processes, and applications described herein canbe made without departing from the scope of any embodiments or aspectsthereof. The compositions and methods provided are exemplary and are notintended to limit the scope of any of the specified embodiments. All ofthe various embodiments, aspects, and options disclosed herein can becombined in any and all variations or iterations. The scope of thecompositions, formulations, methods, and processes described hereininclude all actual or potential combinations of embodiments, aspects,options, examples, and preferences herein described. The exemplarycompositions and formulations described herein may omit any component,substitute any component disclosed herein, or include any componentdisclosed elsewhere herein. The ratios of the mass of any component ofany of the compositions or formulations disclosed herein to the mass ofany other component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. Should the meaning of any terms in any of thepatents or publications incorporated by reference conflict with themeaning of the terms used in this disclosure, the meanings of the termsor phrases in this disclosure are controlling. Furthermore, theforegoing discussion discloses and describes merely exemplaryembodiments. All patents and publications cited herein are incorporatedby reference herein for the specific teachings thereof.

EXAMPLES Example 1

Pharmaceutical compositions as described herein for preventing the overingestion of active pharmaceutical ingredients are illustrated in FIGS.1 and 2.

FIG. 1 represents the anti-over ingestion properties of thepharmaceutical compositions described herein. As shown, when one capsule(2) is ingested into the stomach (1) a controlled release (e.g., animmediate release) of all of the one or more active pharmaceuticalingredients (3) occurs. However, when multiple of the capsules (2) areingested into the stomach (1), a clumping of the capsules (4) occurs,which inhibits the release of the one or more active pharmaceuticalingredients (3), effectively preventing over ingestion of the activepharmaceutical ingredient.

FIG. 2 is a pharmaceutical composition contemplated herein. In oneembodiment described herein, the pharmaceutical composition may be asoft or hard capsule shell containing one or more multiple ionicpolymers (5; 6) encapsulating one or more active pharmaceuticalingredients (3). In another embodiment described herein, the soft orhard capsule shell may not have any ionic polymers. As shown, a positivepolymer (5) may be used in at least a portion of the soft capsule shelland a negative polymer (6) may be used in at least a portion of the softcapsule shell in those compositions containing multiple ionic polymers.The active pharmaceutical ingredient (3) (e.g., an abuse prone drug;oxycodone) may further be in a polyelectrolyte complex. In some aspectsdescribed herein, this polyelectrolyte complex is a cation or anionexchange complex, which further inhibits the release of the activepharmaceutical ingredient (3) when multiple dosage forms are dissolvedin proximity of each other. The cation or anion exchange complex maycomprise a positive cation or a negative anion exchanger. An exemplarypositive cation exchanger polymer with carboxylic acid groups (8) isshown.

The pharmaceutical composition described herein may further comprise anabuse deterrent matrix (7), which prevents the crushing, grating,grinding, cutting, solvating, or dissolving of one or more activepharmaceutical ingredients. An additional means (9) for obtaininggastroretentive properties to the pharmaceutical composition may beincluded in the matrix fill or alternatively in the capsule shell (notillustrated). Exemplary and non-limiting means for gastroretentiveproperties known in the art may comprise one or more of an effervescentgas generating system, a colloidal gel barrier, porous beads, amicroporous membrane, or the inclusion of one or more low-densityexcipients.

Example 2

Weak and strong cation exchange resins and a bound surrogate drug(dextromethorphan) were evaluated for use in an abuse deterrentcomposition. Biochemically similar opioids contemplated herein willdemonstrate similar behaviors and release kinetics. The first resin usedwas strongly acidic and is based on polystyrene sulfonate (Amberlite™IRP69) and a weakly acidic resin that is based on carboxylic acidfunctional groups (Amberlite™ IRP88). Drug-resinates were preparedaccording to the following process: a solution of drug in deionizedwater was mixed with an ion-exchange resin. Typically, a 1:1 ratio ofresin to drug was used. The resinate complex was then separated from theremaining solution by filtration or centrifugation and the resultingresinate was washed several times with DI water and dried in a vacuum.Several batches of resinates of dextromethorphan with Amberlite™ IRP88or Amberlite™ IRP69 were prepared and encapsulated in a hard capsule.

The in vitro drug release from drug-resinates was assessed in simulatedgastrointestinal fluid mediums and in medias having different pH values.The in vitro drug release from drug-resinates at pH: 1.5, 4.8 and 7.4was assessed using the USP basket method (APP I) at 100 rpm in 900 mL ofmedia. The drug release profile with either a drug load of 41 mg fromAmberlite™ IRP69 and Amberlite™ IRP88 is shown in FIGS. 3 and 4,respectively.

The in vitro drug release from drug-resinate was assessed in DI water todemonstrate that the observed drug release from FIGS. 3 and 4 isresulting from the exchange of bound drug ions by ions normally presentin body fluids. This test was carried out using the basket method (APPI) at 100 rpm in 900 mL with a dextromethorphan Amberlite™ IRP69 orAmberlite™ IRP88 resinate as shown in FIG. 5. The drug release in DIwater is negligible suggesting that drug release occurs only in thepresence of ions in the media. Drug release in boiling DI water and inboiling tap water was also negligible as shown in FIGS. 6 and 7.

Dissolution experiments for 200 mg dextromethorphan Amberlite™ IRP69 orAmberlite™ IRP88 resinates were also performed in simulated gastricfluid without pepsin. A stock solution was made with 2 g of NaCl in 7 mLof HCl and DI water to make 1000 mL of SGF at pH 1.2. The releaseprofiles of dextromethorphan from two-piece hard shell capsulescontaining 200 mg of the dextromethorphan-resinate complexes are shownin FIGS. 8 and 9. These data show a pronounced effect of ionconcentration on the release of dextromethorphan from Amberlite™ IRP69(FIG. 8), while there is almost no difference in release between 100%SGF and 5% SGF from the weaker Amberlite™ IRP88 (FIG. 9).

Overingestion or taking of more than the prescribed amount ofpharmaceuticals is a common method of abuse. To test the anti-overingestion properties of the pharmaceutical composition, multiplecapsules were combined in a single reaction vessel and percentage of APIreleased was measured. The Amberlite™ IRP69 composition was tested basedupon its demonstrated ion-specific release profile. The in vitrodissolutions studies of dextromethorphan from Amberlite™ IRP69 frommultiple capsules (1, 5, and 10) were carried out in 0.1 HCl with each200 mg capsule containing 40 mg of the drug. As shown in FIG. 10, theamount of the drug released from 1 capsule was about 40 mg.Surprisingly, however, the amount of drug release was significantlylower than expected for multiple capsules dissolved simultaneously; 5capsules released only 120 mg (theoretical amount should be about 200mg) and 10 capsules released about 150 mg (theoretical amount should beabout 400 mg). This result suggests that there is a ceiling effect forthe dissolution of multiple capsules at once and suggests an alternativemechanism for preventing the overingestion of abuse prone active agents(e.g., oxycodone).

An additional experiment was performed to support the concept that theceiling effect was not caused by solubility/sink limitation, but ratherby retention by sequestering. As shown in FIG. 11, a single capsulewithout resin having 40 mg of dextromethorphan or 10 capsules withoutresin comprising a total amount of 400 mg of dextromethorphan had a doseproportional release. This result suggests that the observed ceilingeffect is not restricted by any solubility or sink limitation, butrather imparted by the presence of a sequestering effect of the resin.

Next, the possibility to gain the same sequestering effect usingphysical blend of drug with resin instead of drug resinate complex wasexplored. The results presented in FIGS. 12 and 13 show that the releaseof dextromethorphan in the presence of Amberlite™ IRP69 is significantlylower compared to those obtained in the presence of Amberlite™ IRP88.This effect is more pronounced for 10 capsules containing 10-fold doseof Amberlite™ IRP69 in the same vessel as compared to 1 capsule pervessel. These findings are consistent with the results obtained with thedextromethorphan-Amberlite™ IRP69-resinate results.

The dissolution of hard capsules having a dextromethorphan-Amberlite™IRP69-resinate and percent release of dextromethorphan was measured withmedia replacement every 15 minutes for 1, 5, and 10 capsules. As shownin FIG. 14, the percent release for 1, 5, and 10 capsules is verysimilar with and without media replacement with a small percent releasedelta at 120 minutes (Δ₁₂₀) (Table 11).

TABLE 11 Delta between dextromethorphan-Amberlite ™ IRP69-resinatewith/without media replacement No. Capsules Δ₁₂₀ (mg) 1 4.3 15 20.1 1033

Example 3

Next, the release of dextromethorphan from a drug-resinate ordrug-physical blend complexes in abuse deterrent matrices were preparedand tested. These matrices were tested in the in vitro-in vivorelationship (IVIVR) dissolution method as shown in Table 12.

TABLE 12 In Vitro-In Vivo Relationship Testing Parameters Apparatus USPApparatus III Agitation rate 30 dips per minute (DPM) Temperature 37.0 ±0.5° C. Media volume 250 mL Media 2 hours FaSSGF; 10 hours FaSSIF Pullvolume 2 mL Profiled sampling times 1, 2, 4, 8, and 12 hours

An abuse deterrent composition as shown in Table 13 was prepared by thefollowing method. First, the specified amount of PEG 400 and Methocel™A4M was dispensed in a beaker and let it hydrated for about an hour.Next the specified amount of soybean oil was heated to about 140° C. andthe specified amount of Ethocel™ (20 cP) was added and mixed until aclear solution was obtained. The oil/ Ethocel™ (20 cP) mixture wascooled to about 90° C. and the specified amount of carnauba wax andyellow bees wax was added and mixed until dissolved and the resultingsolution was cooled to room temperature. The PEG 400 and Methocel™ A4Mmixture was then added to the oil and wax mixture to obtain a uniformmix. This mixture was then homogenized for approximately 5 minutes untila smooth final fill mixture was obtained. A total of 4 g ofdextromethorphan/Amberlite™ IRP88 resinate was added to 20 g ofcomposition as shown in Table 13.

TABLE 13 Exemplary Abuse Deterrent Controlled Release CompositionComponents Mass (mg/capsule) Percentage (%) Soybean Oil 546 65 Ethocel ™(4 cP) 14 1.7 Carnauba Wax 17.5 2.0 Bee's Wax 17.5 2.0 Methocel ™ A4M52.5 6.3 Polyethylene Glycol 400 52.5 6.3 Dextromethorphan/resinate 14016.7 TOTAL 840 100

Example 4

Several abuse deterrent hydrogel formulations based on an abusedeterrent composition with a dextromethorphan/resinate complex weredeveloped as shown in Tables 14-17. These compositions were then filledin a hard shell capsule for further dissolution testing using thedissolution apparatus III with the parameters shown in Table 12. Thecomposition shown in Table 14 was supplemented with the adhesive polymer5% polycarbophil (composition of Table 16) and about 50 mgdextromethorphan was complexed with about 50 mg of Amberlite™ IRP88 (1:1ratio) as a resinate and tested by the same parameters. As shown in FIG.15, a modest decrease in drug release was observed after 5 capsules weredissolved together in matrices containing PCP; the theoretical releaseis about 250 mg and 217 mg release was actually observed.

The release of dextromethorphan from the composition according to Table14 comprising 75 mg of Amberlite™ IRP69 and 25 mg of dextromethorphan ina resinate was tested. The addition of Polycarbophil according to thecomposition of Table 16 was added as an adhesive polymer to theAmberlite™ IRP69-dextromethorphan resinate to determine if the additionof polycarbophil promotes additional over ingestion ceiling effects inthese compositions. As shown in FIG. 16, the dissolution of 1 capsuleresulted in about 25 mg of dissolved dextromethorphan and thedissolution of 5 capsules resulted in the dissolution of 70-76 mg ofdextromethorphan. There was a modest decrease in drug release with theaddition of polycarbophil.

Next, the Amberlite™ IRP69-dextromethorphan blends with 25 mg ofdextromethorphan and 75 mg of Amberlite™ IRP69 were tested. As shown inFIG. 17, these physical blends demonstrated a markedly decreased releaserate for both 1 capsule and 5 capsules compared to the resinate blendsshown in FIG. 16.

TABLE 14 Exemplary Abuse Deterrent Controlled Release CompositionComponents Mass (mg/capsule) Percentage (%) Polyethylene Glycol 400662.5 66.3 Polyethylene Glycol 1000 92.5 9.3 PVP K90 12.5 1.3 Carbopol ®974P 12.5 1.3 HPMC K100M 120 12 Dextromethorphan/resinate 100 10 TOTAL1000 100

TABLE 15 Exemplary Abuse Deterrent Controlled Release CompositionComponents Mass (mg/capsule) Percentage (%) Polyethylene Glycol 400 46360.2 Polyethylene Glycol 1000 64.8 8.4 PVP K90 8.8 1.1 Carbopol ® 974P8.8 1.1 HPMC K100M 84 10.9 Dextromethorphan/resinate 140 18.2 TOTAL 770100

TABLE 16 Exemplary Abuse Deterrent Controlled Release CompositionComponents Mass (mg/capsule) Percentage (%) Polyethylene Glycol 400 62962.95 Polyethylene Glycol 1000 88 8.8 PVP K90 12 1.2 Carbopol ® 974P 121.2 HPMC K100M 114 11.4 Polycarbophil 50 5 Dextromethorphan/resinate 959.5 TOTAL 1050 100

TABLE 17 Exemplary Abuse Deterrent Controlled Release CompositionComponents Mass (mg/capsule) Percentage (%) Polyethylene Glycol 400461.7 57 Polyethylene Glycol 1000 64.8 8 PVP K90 9.7 1.2 Carbopol ® 974P9.7 1.2 HPMC K100M 84.2 10.4 Polycarbophil 40.5 5Dextromethorphan/resinate 140.1 17.3 TOTAL 810 100

Example 5

Exemplary soft capsules shells for encapsulating an abuse deterrentcomposition described herein, which in some aspects function to furtherlimit the over ingestion of abuse prone drugs were designed. These softcapsule shells prevent over ingestion by promoting clumping of the oneor more dosage forms, which limits drug dissolution out of the matricesdescribed herein. These soft capsules have multiple charged ionicpolymers that may be either integrated within the capsule gel mass orcoated on a formed soft capsule. As described below, a soft gelatincapsule was generated and approximately half of the soft capsule shellwas coated with a coating composition that comprises a negative polymerand the other half was coated with a coating composition that comprisesa positive polymer as shown in Table 18.

TABLE 18 Exemplary Dual Charged Soft Capsule Shell Coatings PositiveNegative Coating Percentage Coating Percentage Components (%) (%)Gelatin 26 29.2 Methacrylic Acid Copolymer — 11.2 (EUDRAGIT ® L 100)Dimethylaminoethyl 12 — Methacrylate Copolymer (EUDRAGIT ® EPO) Glycerol16.5 18 Triethyl citrate 1.3 HCl 0.5 — Ammonium hydroxide — 1.7 Titaniumdioxide — 1.5 Water 44.2 37.1 TOTAL 100 100

Example 6

An exemplary anti-overingestion formulation was prepared by combining a1:4 mass ratio of dry hydrocodone bitartrate and dry sodium polystyrenesulfonate IRP69 resin (e.g., Amberlite™ IRP69) and blending to form apowder suspension (Table 19). The resulting powder was filled into size4 hard shell capsules to provide a dosage form comprising 5 mghydrocodone bitartrate. This formulation provides an immediate releasenon-resin bound pharmaceutical composition.

TABLE 19 Anti-Overingestion Formulation Weight Percent Component Mass(mg) (%) Hydrocodone Bitartrate 5 20% Sodium polystyrene sulfonate 2080% IRP69* TOTAL 25 mg 100% API: Resin Ratio 1:4 *AMBERLITE ™ IRP69 USP,sulfonated copolymer of stryene and divinylbenzene, pharmaceutical gradestrong cation exchange resin; size 4 hard capsule

A control composition comprising only the active pharmaceuticalingredient was also prepared (Table 20). Each hard capsule dosage formprovides 5 mg of hydrocodone bitartrate.

TABLE 20 Anti-Overingestion Control Component Mass (mg) Weight Percent(%) Hydrocodone Bitartrate 5 100% TOTAL 5 mg 100% Size 4 hard capsule

Example 7

Analytical analyses were performed on the composition shown in Table 19and a control composition lacking the sodium polystyrene sulfonate IRP69shown in Table 20.

TABLE 21 Analytical Analysis of Anti-Overingestion FormulationTest/Methods Acceptable limits Results Test Sample (Table 19)hydrocodone bitartrate immediate release capsules with sodiumpolystyrene sulfonate IRP69, 5 mg API Physical Description Two pice hardshell capsule, no Pass printing; tan powder Identification Retentiontime of sample is Pass (HPLC; PD16-275) between 0.98 and 1.02 relativeto average retention time of standard hydrocodone bitartrate Assay(PD16-275) Report results 99.9% Control Sample (Table 20) hydrocodonebitartrate immediate release capsules, 5 mg API Physical Description Twopice hard shell capsule, no Pass printing; white powder IdentificationRetention time of sample is Pass (HPLC; PD16-275) between 0.98 and 1.02relative to average retention time of standard hydrocodone bitartrateAssay (PD16-275) Report results 99.9%

Example 8 Pharmacokinetic Crossover Study of Two Orally AdministeredHydrocodone Formulations in Beagle Dogs

A pharmacokinetic study was conducted using the formulations shown inTable 19 comprising 5 mg hydrocodone bitartrate and 20 mg of Amberlite™IRP69. Control samples contained 5 mg hydrocodone bitartrate (no resin;Table 20).

A total of six male beagle dogs were assigned to the study. The sameanimals were used for each phase, with a minimum 3-day washout periodbetween dosing in each phase. For each phase, all animals were fastedfor at least eight hours prior to dosing and through the first fourhours of blood sample collection, (food was returned 30 minutesfollowing collection of the last blood sample at the 4-hour collectioninterval). The total fasting time did not exceed 24 hours.

For each phase, one animal per group (Groups 1-6) received an oralcapsule dose of the appropriate Test formulation or Control formulationas outlined in Tables 22-23. Animals were dosed in a latin-squaredesign, with each animal receiving each of six treatments once in arotating fashion, as outlined below. For each dose, at approximately 30minutes (±5 minutes) prior to test article administration, each animalreceived 25 mg of naltrexone (one half of a 50 mg tablet) to block theopioid effects of the test article. In addition, naloxone (0.02-0.04mg/kg, IV) was available as a rescue medication, if opiate overdoseeffects (e.g., respiratory depression) were noted following test articleadministration.

Blood samples, 0.5 mL/sample, were collected in K₂EDTA vacutainers fromthe jugular vein at the following times: predose (0) and 0.25, 0.5,0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12 and 14-hours postdose. Allblood samples were placed on wet ice following collection untilcentrifuging and plasma was isolated. Plasma samples were analyzed forthe concentration of test article over the applicable range (e.g., 1ng/mL to 1,000 ng/mL) using a HPLC mass spectrometry (HPLC MS/MS)method.

All animals were observed at least twice a day for morbidity, mortality,injury, and availability of food and water. Any animals in poor healthwere identified for further monitoring and possible euthanasia. For eachdose, body weights were measured and recorded on the day of dosing orthe day prior to dosing. A detailed clinical examination for each animalwas performed pretest and relevant observations were recorded.

A model independent method was used to determine C_(max), T_(max) andAUC values for the test article from concentration-time data in the Testspecies. Based on the data, appropriate parameters were estimatedincluding: C_(max)/Dose, AUC_(Tlast), AUC_(0-τ), AUC/Dose, and ControlRatio (at each dose level tested)=AUC_(Test)/AUC_(Control).

Results are shown in Tables 24-25.

TABLE 22 Study Design Parameters Dose Dose Level Dose Amount CollectionGroups Treatment Number Route (mg/animal) (capsule/animal) Interval 1-6Test 1

Oral 5, 25, or 50 1, 5, or 10 Blood^(†) Hydrocodone- animal/ Capsule* mgas capsules as Resin or group specified specified Hydrocodone Control*All animals were pretreated with a single oral tablet 25 mg dose ofnaltrexone prior to test article administration in each phase. Allcapsules had 5 mg hydrocodone bitartrate per capsule. ^(†)Blood sampleswere collected predose (0) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3,4, 6, 8, 10, 12 and 14-hours postdose.

TABLE 23 Dosing Protocol (male beagle dogs) Treatment Phase 1 Phase 2Phase 3 Phase 4 Phase 5 Phase 6 Dose Dose Dose Dose Dose Dose Grp (mg)Qant.^(#) (mg) Qant.^(#) (mg) Qant.^(#) (mg) Qant.^(#) (mg) Qant.^(#)(mg) Qant.^(#) 1 5 T^(a) 1 25 T 5 50 T 10 5 C 1 25 C 5 50 C 10 2 25 T 550 T 10 5 C 1 25 C 5 50 C 10 5 T 1 3 50 T 10 5 T 1 25 C 5 50 C 10 5 T 125 T 5 4 5 C^(b) 1 25 C 5 50 C 10 5 T 1 25 T 5 50 T 10 5 25 C 5 50 C 105 T 1 25 T 5 50 T 10 5 C 1 6 50 C 10 5 C 1 25 T 5 50 T 10 5 C 1 25 C 5^(a)T = Test dosage form containing 20 mg Amberlite ™ IRP69 resin and 5mg of hydrocodone bitartrate per capsule. ^(b)C = Control dosage formcontaining 5 mg of hydrocodone bitartrate per capsule. ^(#)Number ofcapsules administered per animal; all capsules contain 5 mg ofhydrocodone bitartrate per capsule.

Table 24 shows the average hydrocodone plasma concentration as afunction of time for the Test and Control compositions at 5 mg, 25 mg,and 50 mg doses. These data are plotted in FIG. 18.

TABLE 24 Average Plasma Hydrocodone Concentrations for Test and ControlDoses in Male Dogs Time Test Control (h) 5 mg 25 mg 50 mg 5 mg 25 mg 50mg 0.0 0.5 0.0 0.4 0.3 0.4 0.7 0.25 1.2 2.4 1.6 5.6 11.6 34.4 0.5 2.914.0 17.1 11.8 88.2 152.6 0.75 5.9 57.7 39.8 23.6 91.5 174.1 1.0 12.258.3 68.7 17.7 99.1 150.7 1.25 13.1 95.2 93.0 26.6 106.9 175.9 1.5 18.698.6 145.1 23.4 90.4 187.3 2.0 20.8 77.7 150.0 19.7 72.2 162.0 3.0 12.147.2 91.0 10.1 38.9 77.4 4.0 5.7 25.7 60.0 5.6 24.6 48.6 6.0 1.7 10.924.8 1.8 7.4 14.2 8.0 0.8 5.4 11.9 0.8 3.0 7.6 10.0 0.6 3.3 7.7 0.2 1.84.1 12.0 0.4 2.3 6.3 0.5 1.3 3.2 14.0 0.6 1.6 5.4 0.3 0.6 2.2

TABLE 25 Pharmacokinetic Parameters Following a Single OralAdministration of 5, 25, or 50 mg Hydrocodone and Resin (T) orHydrocodone Control (C) to Male Beagle Dogs AUC_(0-14 hr)/ C_(max)/doseDose Test: C_(max) (ng/ T_(max) T_(last) AUC_(Tlast) AUC_(0-14 hr) (hr *ng/ Control Treatmt Stat (ng/mL) mL/mg) (hr)^(a) (hr)^(a) (hr · ng/mL)(hr · ng/mL) mL/mg) Ratio^(b)  5 mg T N 6 6 6 6 6 6 6 6 Mean 26.3 5.25NA 6 57.1 59.6 11.9 0.953 SD 6.53 1.31   (1-2) (4-14) 19.7 18.5 3.690.567 CV % 24.9 24.9 NA NA 34.6 30.9 30.9 59.5 25 mg T N 6 6 6 6 6 6 6 6Mean 105 4.21 NA NA 282 283 11.3 1.01 SD 29.4 1.18 (0.75- (10- 67.7 67.72.71 0.313 1.5) 14) CV % 27.9 27.9 NA NA 24.0 23.9 23.9 31.1 50 mg T N 66 6 6 6 6 6 5 Mean 178 3.57 1.5 14 510 510 10.2 0.834 SD 71.5 1.43  (1-2) (14- 182 182 3.63 0.168 14) CV % 40.1 40.1 NA NA 35.7 35.7 35.720.1  5 mg C N 6 6 6 6 6 6 6 NA Mean 36.2 7.24 NA 6 68.5 70.3 14.1 NA SD14.0 2.81 (0.75-2)  (4-14) 20.3 19.7 3.95 NA CV % 38.8 38.8 NA NA 29.728.1 28.1 NA 25 mg C N 6 6 6 6 6 6 6 NA Mean 150 6.01 1 NA 290 291 11.6NA SD 41.1 1.64 (0.5-2) (8-14) 58.3 57.6 2.31 NA CV % 27.3 27.3 NA NA20.1 19.8 19.8 NA 50 mg C N 5 5 5 5 5 5 5 NA Mean 300 6.00 1.5 14 591592 11.8 NA SD 163 3.26 (0.5-2) (12- 111 110 2.20 NA 14) CV % 54.4 54.4NA NA 18.7 18.6 18.6 NA NA: Not applicable. ^(a)Median(minimum-maximum), median value only reported if actual collectioninterval. ^(b)Test: Control Ratio = AUC_(0-14hr) Test/AUC_(0-14 hr)Control.

Results are shown in FIGS. 18-19.

TABLE 26 Individual Pharmacokinetic Parameters Following a Single OralAdministration of 5, 25, or 50 mg Hydrocodone and Resin (T) orHydrocodone Control (C) to Male Beagle Dogs AUC_(0-14 hr)/ Dose Test:C_(max) C_(max)/dose T_(max) T_(last) AUC_(Tlast) AUC_(0-14 hr) (hr *ng/ Control Treat. Gender Subject (ng/mL) (ng/mL/mg) (hr)^(a) (hr) (hr ·ng/mL) (hr · ng/mL) mL/mg)^(a) Ratio^(a)  5 mg T

101 18.5 3.70 2 6 40.1 41.8 8.36 0.658

102 37.4 7.48 1 8 62.7 64.1 12.8 1.18

103 27.0 5.40 1.5 14 91.2 91.2 18.2 2.00

104 22.8 4.56 1 6 60.3 62.1 12.4 0.627 25 mg T

105 28.8 5.76 2 4 51.6 58.0 11.6 0.747

106 23.1 4.62 2 4 36.5 40.7 8.13 0.494

101 107 4.28 1.5 12 279 281 11.2 0.787

102 108 4.32 0.75 12 294 295 11.8 1.09 50 mg T

103 91.0 3.64 1 14 264 264 10.6 1.29

104 145 5.80 1.5 14 399 399 16.0 1.43

105 122 4.88 1.25 10 269 270 10.8 0.763

106 57.9 2.32 1.5 14 189 189 7.56 0.673  5 mg C

101 23.5 4.70 2 6 62.2 63.5 12.7 0.783

102 43.2 8.64 1.25 4 49.6 54.1 10.8 0.895

103 24.5 4.90 1.5 6 44.3 45.5 9.10 0.673

104 33.1 6.62 1 8 97.6 99.0 19.8 1.10 25 mg C

105 60.9 12.2 0.75 4 75.0 77.6 15.5 NA

106 32.0 6.40 0.75 14 82.4 82.4 16.5 0.723

101 168 6.72 0.5 14 357 357 14.3 0.658

102 85.0 3.40 2 12 267 270 10.8 1.18 50 mg C

103 124 4.96 1.25 8 202 204 8.17 2.00

104 203 8.12 0.5 8 277 279 11.1 0.627

105 152 6.08 1.5 10 353 354 14.2 0.747

106 170 6.80 0.75 14 281 281 11.3 0.494 NA: Not applicable. ^(a)Test:Control Ratio = AUC_(0-14 hr) Test/AUC_(0-14 hr) Control

Table 27 shows the difference (absolute value) and percentage differencefor C_(max) AUC_(0-14 hr) between the Test and Control data shown inTable 24

TABLE 27 Differences between Test and Control Pharmacokinetic Parametersat Each Dose Dose C_(max) Test C_(max) Control Difference % Difference 5 mg 26.3 36.2 9.9 31.7% 25 mg 105 150 45 35.3% 50 mg 178 300 122 51.1%Dose AUC₀₋₁₄ Test AUC₀₋₁₄ Control Difference % Difference  5 mg 59.670.3 10.7 16.5% 25 mg 283 291 8  2.8% 50 mg 510 592 82 14.9%

What is claimed is:
 1. An oral immediate release composition comprising:one or more active pharmaceutical ingredients (API) and one or morestrong cation exchange resins capable of interacting with the API at amass ratio of about 1:2 to about 1:8; less than 1% of the API is boundto the strong cation exchange resin prior to solvation; and aftersolvation of two more doses of the composition simultaneously orsuccessively over about a 4-hour period, the strong cation exchangeresin adsorbs about 15% to about 70% by mass of the API and impedes itsabsorption into a subject's systemic circulation, lowering C_(max) forthe API by about 30% to about 50% as compared to an equivalent dose ofthe API lacking a strong cation exchange resin.
 2. The composition ofclaim 1, wherein the mass ratio of API to strong cation exchange resinis about 1:4.
 3. The composition of claim 1, wherein the compositioncomprises a dry powder.
 4. The composition of claim 1, wherein thecomposition is non-layered.
 5. The method of claim 1, wherein thecomposition is encapsulated in a capsule or formed as a tablet.
 6. Thecomposition of claim 1, wherein the composition futher comprises one ormore pharmaceutically acceptable excipients.
 7. The composition of claim1, wherein subjects administered the composition exhibit one or more ofthe following pharmacokinetic parameters: (a) a delayed T_(max) for theAPI as compared to an equivalent API dose lacking a strong cationexchange resin; (b) a lower plasma AUC for the API as compared to anequivalent API dose lacking a strong cation exchange resin; (c) anextended absorption time for the API as compared to an equivalent APIdose lacking a strong cation exchange resin; or (d) an extendedclearance time for the API as compared to an equivalent API dose lackinga strong cation exchange resin.
 8. The composition of claim 1, whereinthe composition comprises: about 10% to about 30% by mass of API; andabout 70% to 90% by mass of a strong cation exchange resin.
 9. Thecomposition of claim 1, wherein the composition comprises: about 20% bymass of API; and about 80% by mass of a strong cation exchange resin.10. The composition of claim 1, wherein the composition exhibits an invitro disintegration or dissolution rate comprising about 50%disintegration or dissolution after about 1 minute to about 15 minutesin simulated gastric fluid comprising 34.2 mM NaCl and 0.1 N HCl, pH 1.2using the USP basket method.
 11. The composition of claim 1, whereinsubjects administered the composition exhibit a plasma AUC for the APIof about 15% lower as compared to an equivalent API dose lacking astrong cation exchange resin.
 12. The composition of claim 1, whereinthe strong cation exchange resin comprises polystyrene sulfonate or asalt thereof.
 13. The composition of claim 1, wherein the API comprisesanalgesics, anaesthetics, antimigraine drugs, antiepileptics,anticholinergics, antipsychotics, anxiolytics, hypnotics, sedatives,antidepressants, anti-dementia drugs, or combinations thereof.
 14. Thecomposition of claim 1, wherein the API comprises an opioid agonist. 15.The composition of claim 1, wherein the API comprises hydrocodone,oxycodone, oxymorphone, hydromorphone, morphine, codeine, salts thereof,or combinations thereof.
 16. The composition of claim 1, wherein the APIcomprises hydrocodone or a salt thereof.
 17. A method for mitigating therisk of overingestion of an active pharmaceutical ingredient (API), themethod comprising administering to a subject in need thereof one or moreoral immediate release compositions of claim
 1. 18. A method forregulating the concentration of an active pharmaceutical ingredient in asubject's systemic circulation, the method comprising: administering toa subject one or more oral immediate release compositions of claim 1.19. The method of claim 15, further comprising: (a) acquiring a bodilyfluid from the subject; (b) measuring the concentration of the API inthe subject's circulation; and (c) according to the measured APIconcentration and a desired optimal API therapeutic concentration,either: (i) administering one or more doses of the compositioncomprising the API and the strong cation exchange resin; (ii)administering an equivalent dose of the API comprising a compositionlacking the strong cation exchange resin; or (iii) administering eitherone or more doses of the composition comprising the API and the strongcation exchange resin or administering an equivalent dose of the APIcomprising a composition lacking the strong cation exchange resin aftera period of about 30 min to about 12 hours.
 20. The method of claim 19,where the bodily fluid is blood.